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Smoom R, May CL, Lichtental D, Skordalakes E, Kaestner KH, Tzfati Y. Separation of telomere protection from length regulation by two different point mutations at amino acid 492 of RTEL1. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.26.582005. [PMID: 38464183 PMCID: PMC10925190 DOI: 10.1101/2024.02.26.582005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
RTEL1 is an essential DNA helicase that plays multiple roles in genome stability and telomere length regulation. A variant of RTEL1 with a lysine at position 492 is associated with short telomeres in Mus spretus , while a conserved methionine at this position is found in M. musculus , which has ultra-long telomeres. In humans, a missense mutation at this position ( Rtel1 M492I ) causes a fatal telomere biology disease termed Hoyeraal-Hreidarsson syndrome (HHS). Introducing the Rtel1 M492K mutation into M. musculus shortened the telomeres of the resulting strain, termed 'Telomouse', to the length of human telomeres. Here, we report on a mouse strain carrying the Rtel1 M492I mutation, termed 'HHS mouse'. The HHS mouse telomeres are not as short as those of Telomice but nevertheless they display higher levels of telomeric DNA damage, fragility and recombination, associated with anaphase bridges and micronuclei. These observations indicate that the two mutations separate critical functions of RTEL1: M492K mainly reduces the telomere length setpoint, while M492I predominantly disrupts telomere protection. The two mouse models enable dissecting the mechanistic roles of RTEL1 and the different contributions of short telomeres and DNA damage to telomere biology diseases, genomic instability, cancer, and aging.
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2
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Herr LM, Schaffer ED, Fuchs KF, Datta A, Brosh RM. Replication stress as a driver of cellular senescence and aging. Commun Biol 2024; 7:616. [PMID: 38777831 PMCID: PMC11111458 DOI: 10.1038/s42003-024-06263-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 04/29/2024] [Indexed: 05/25/2024] Open
Abstract
Replication stress refers to slowing or stalling of replication fork progression during DNA synthesis that disrupts faithful copying of the genome. While long considered a nexus for DNA damage, the role of replication stress in aging is under-appreciated. The consequential role of replication stress in promotion of organismal aging phenotypes is evidenced by an extensive list of hereditary accelerated aging disorders marked by molecular defects in factors that promote replication fork progression and operate uniquely in the replication stress response. Additionally, recent studies have revealed cellular pathways and phenotypes elicited by replication stress that align with designated hallmarks of aging. Here we review recent advances demonstrating the role of replication stress as an ultimate driver of cellular senescence and aging. We discuss clinical implications of the intriguing links between cellular senescence and aging including application of senotherapeutic approaches in the context of replication stress.
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Affiliation(s)
- Lauren M Herr
- Helicases and Genomic Integrity Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Ethan D Schaffer
- Helicases and Genomic Integrity Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Kathleen F Fuchs
- Helicases and Genomic Integrity Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Arindam Datta
- Helicases and Genomic Integrity Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
- Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
| | - Robert M Brosh
- Helicases and Genomic Integrity Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
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3
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Kumar N, Taneja A, Ghosh M, Rothweiler U, Sundaresan N, Singh M. Harmonin homology domain-mediated interaction of RTEL1 helicase with RPA and DNA provides insights into its recruitment to DNA repair sites. Nucleic Acids Res 2024; 52:1450-1470. [PMID: 38153196 PMCID: PMC10853778 DOI: 10.1093/nar/gkad1208] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 12/04/2023] [Accepted: 12/06/2023] [Indexed: 12/29/2023] Open
Abstract
The regulator of telomere elongation helicase 1 (RTEL1) plays roles in telomere DNA maintenance, DNA repair, and genome stability by dismantling D-loops and unwinding G-quadruplex structures. RTEL1 comprises a helicase domain, two tandem harmonin homology domains 1&2 (HHD1 and HHD2), and a Zn2+-binding RING domain. In vitro D-loop disassembly by RTEL1 is enhanced in the presence of replication protein A (RPA). However, the mechanism of RTEL1 recruitment at non-telomeric D-loops remains unknown. In this study, we have unravelled a direct physical interaction between RTEL1 and RPA. Under DNA damage conditions, we showed that RTEL1 and RPA colocalise in the cell. Coimmunoprecipitation showed that RTEL1 and RPA interact, and the deletion of HHDs of RTEL1 significantly reduced this interaction. NMR chemical shift perturbations (CSPs) showed that RPA uses its 32C domain to interact with the HHD2 of RTEL1. Interestingly, HHD2 also interacted with DNA in the in vitro experiments. HHD2 structure was determined using X-ray crystallography, and NMR CSPs mapping revealed that both RPA 32C and DNA competitively bind to HHD2 on an overlapping surface. These results establish novel roles of accessory HHDs in RTEL1's functions and provide mechanistic insights into the RPA-mediated recruitment of RTEL1 to DNA repair sites.
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Affiliation(s)
- Niranjan Kumar
- Molecular Biophysics Unit, Indian Institute of Science, Bengaluru 560012, India
| | - Arushi Taneja
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru 560012, India
| | - Meenakshi Ghosh
- Molecular Biophysics Unit, Indian Institute of Science, Bengaluru 560012, India
| | - Ulli Rothweiler
- The Norwegian Structural Biology Centre, Department of Chemistry, The Arctic University of Norway, N-9037, Tromsø, Norway
| | | | - Mahavir Singh
- Molecular Biophysics Unit, Indian Institute of Science, Bengaluru 560012, India
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Hourvitz N, Awad A, Tzfati Y. The many faces of the helicase RTEL1 at telomeres and beyond. Trends Cell Biol 2024; 34:109-121. [PMID: 37532653 DOI: 10.1016/j.tcb.2023.07.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 07/01/2023] [Accepted: 07/05/2023] [Indexed: 08/04/2023]
Abstract
Regulator of telomere elongation 1 (RTEL1) is known as a DNA helicase that is important for telomeres and genome integrity. However, the diverse phenotypes of RTEL1 dysfunction, the wide spectrum of symptoms caused by germline RTEL1 mutations, and the association of RTEL1 mutations with cancers suggest that RTEL1 is a complex machine that interacts with DNA, RNA, and proteins, and functions in diverse cellular pathways. We summarize the proposed functions of RTEL1 and discuss their implications for telomere maintenance. Studying RTEL1 is crucial for understanding the complex interplay between telomere maintenance and other nuclear pathways, and how compromising these pathways causes telomere biology diseases, various aging-associated pathologies, and cancer.
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Affiliation(s)
- Noa Hourvitz
- Department of Genetics, The Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Safra Campus, Jerusalem 91904, Israel
| | - Aya Awad
- Department of Genetics, The Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Safra Campus, Jerusalem 91904, Israel
| | - Yehuda Tzfati
- Department of Genetics, The Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Safra Campus, Jerusalem 91904, Israel.
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5
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De Piante E, D'Aria F, Napolitano LMR, Amato J, Pirrello S, Onesti S, Giancola C. Exploring the G-quadruplex binding and unwinding activity of the bacterial FeS helicase DinG. Sci Rep 2023; 13:12610. [PMID: 37537265 PMCID: PMC10400533 DOI: 10.1038/s41598-023-39675-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 07/28/2023] [Indexed: 08/05/2023] Open
Abstract
Despite numerous reports on the interactions of G-quadruplexes (G4s) with helicases, systematic analysis addressing the selectivity and specificity of each helicase towards a variety of G4 topologies are scarce. Among the helicases able to unwind G4s are those containing an iron-sulphur (FeS) cluster, including both the bacterial DinG (found in E. coli and several pathogenic bacteria) and the medically important eukaryotic homologues (XPD, FancJ, DDX11 and RTEL1). We carried out a detailed study of the interactions between the E. coli DinG and a variety of G4s, by employing physicochemical and biochemical methodologies. A series of G4-rich sequences from different genomic locations (promoter and telomeric regions), able to form unimolecular G4 structures with diverse topologies, were analyzed (c-KIT1, KRAS, c-MYC, BCL2, Tel23, T30695, Zic1). DinG binds to most of the investigated G4s with little discrimination, while it exhibits a clear degree of unwinding specificity towards different G4 topologies. Whereas previous reports suggested that DinG was active only on bimolecular G4s, here we show that it is also able to bind to and resolve the more physiologically relevant unimolecular G4s. In addition, when the G4 structures were stabilized by ligands (Pyridostatin, PhenDC3, BRACO-19 or Netropsin), the DinG unwinding activity decreased and in most cases was abolished, with a pattern that is not simply explained by a change in binding affinity. Overall, these results have important implications for the biochemistry of helicases, strongly suggesting that when analysing the G4 unwinding property of an enzyme, it is necessary to investigate a variety of G4 substrates.
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Affiliation(s)
- Elisa De Piante
- Structural Biology Laboratory, Elettra-Sincrotrone Trieste S.C.p.A, 34149, Trieste, Italy
- Department of Pharmacy, University of Naples Federico II, 80131, Naples, Italy
| | - Federica D'Aria
- Department of Pharmacy, University of Naples Federico II, 80131, Naples, Italy
| | - Luisa M R Napolitano
- Structural Biology Laboratory, Elettra-Sincrotrone Trieste S.C.p.A, 34149, Trieste, Italy
| | - Jussara Amato
- Department of Pharmacy, University of Naples Federico II, 80131, Naples, Italy
| | - Simone Pirrello
- Structural Biology Laboratory, Elettra-Sincrotrone Trieste S.C.p.A, 34149, Trieste, Italy
| | - Silvia Onesti
- Structural Biology Laboratory, Elettra-Sincrotrone Trieste S.C.p.A, 34149, Trieste, Italy.
| | - Concetta Giancola
- Department of Pharmacy, University of Naples Federico II, 80131, Naples, Italy.
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Datta A, Sommers JA, Jhujh SS, Harel T, Stewart GS, Brosh RM. Discovery of a new hereditary RECQ helicase disorder RECON syndrome positions the replication stress response and genome homeostasis as centrally important processes in aging and age-related disease. Ageing Res Rev 2023; 86:101887. [PMID: 36805074 PMCID: PMC10018417 DOI: 10.1016/j.arr.2023.101887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 02/02/2023] [Accepted: 02/15/2023] [Indexed: 02/22/2023]
Abstract
Characterizing the molecular deficiencies underlying human aging has been a formidable challenge as it is clear that a complex myriad of factors including genetic mutations, environmental influences, and lifestyle choices influence the deterioration responsible for human pathologies. In addition, the common denominators of human aging, exemplified by the newly updated hallmarks of aging (López-Otín et al., 2023), suggest multiple avenues and layers of crosstalk between pathways important for genome and cellular homeostasis, both of which are major determinants of both good health and lifespan. In this regard, we postulate that hereditary disorders characterized by chromosomal instability offer a unique window of insight into aging and age-related disease processes. Recently, we discovered a new RECQ helicase disorder, designated RECON syndrome attributed to bi-allelic mutations in the RECQL1 gene (Abu-Libdeh et al., 2022). Cells deficient in RECQL1 exhibit genomic instability and a compromised response to replication stress, providing further evidence for the significance of genome homeostasis to suppress disease phenotypes. Here we provide a perspective on the pathology of RECON syndrome to inform the reader as to how molecular defects in the RECQL1 gene contribute to underlying deficiencies in nucleic acid metabolism often seen in certain aging or age-related diseases.
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Affiliation(s)
- Arindam Datta
- Helicases and Genomic Integrity Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA
| | - Joshua A Sommers
- Helicases and Genomic Integrity Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA
| | - Satpal S Jhujh
- Institute for Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Tamar Harel
- Department of Genetics, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Grant S Stewart
- Institute for Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Robert M Brosh
- Helicases and Genomic Integrity Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.
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7
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Weeks-Pollenz SJ, Ali Y, Morris LA, Sutera VA, Dudenhausen EE, Hibnick M, Lovett ST, Bloom LB. Characterization of the Escherichia coli XPD/Rad3 iron-sulfur helicase YoaA in complex with the DNA polymerase III clamp loader subunit chi (χ). J Biol Chem 2023; 299:102786. [PMID: 36509145 PMCID: PMC9826845 DOI: 10.1016/j.jbc.2022.102786] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 12/02/2022] [Accepted: 12/05/2022] [Indexed: 12/14/2022] Open
Abstract
Escherichia coli YoaA aids in the resolution of DNA damage that halts DNA synthesis in vivo in conjunction with χ, an accessory subunit of DNA polymerase III. YoaA and χ form a discrete complex separate from the DNA polymerase III holoenzyme, but little is known about how YoaA and χ work together to help the replication fork overcome damage. Although YoaA is predicted to be an iron-sulfur helicase in the XPD/Rad3 helicase family based on sequence analysis, the biochemical activities of YoaA have not been described. Here, we characterize YoaA and show that purified YoaA contains iron. YoaA and χ form a complex that is stable through three chromatographic steps, including gel filtration chromatography. When overexpressed in the absence of χ, YoaA is mostly insoluble. In addition, we show the YoaA-χ complex has DNA-dependent ATPase activity. Our measurement of the YoaA-χ helicase activity illustrates for the first time YoaA-χ translocates on ssDNA in the 5' to 3' direction and requires a 5' single-stranded overhang, or ssDNA gap, for DNA/DNA unwinding. Furthermore, YoaA-χ preferentially unwinds forked duplex DNA that contains both 3' and 5' single-stranded overhangs versus duplex DNA with only a 5' overhang. Finally, we demonstrate YoaA-χ can unwind damaged DNA that contains an abasic site or damage on 3' ends that stall replication extension. These results are the first biochemical evidence demonstrating YoaA is a bona fide iron-sulfur helicase, and we further propose the physiologically relevant form of the helicase is YoaA-χ.
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Affiliation(s)
- Savannah J Weeks-Pollenz
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA
| | - Yasmin Ali
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA
| | - Leslie A Morris
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA
| | - Vincent A Sutera
- Department of Biology and Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Massachusetts, USA
| | - Elizabeth E Dudenhausen
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA
| | - Margaret Hibnick
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA
| | - Susan T Lovett
- Department of Biology and Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Massachusetts, USA
| | - Linda B Bloom
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA.
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8
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Datta A, Brosh RM. WRN rescues replication forks compromised by a BRCA2 deficiency: Predictions for how inhibition of a helicase that suppresses premature aging tilts the balance to fork demise and chromosomal instability in cancer. Bioessays 2022; 44:e2200057. [PMID: 35751457 PMCID: PMC9527950 DOI: 10.1002/bies.202200057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 06/03/2022] [Accepted: 06/08/2022] [Indexed: 11/08/2022]
Abstract
Hereditary breast and ovarian cancers are frequently attributed to germline mutations in the tumor suppressor genes BRCA1 and BRCA2. BRCA1/2 act to repair double-strand breaks (DSBs) and suppress the demise of unstable replication forks. Our work elucidated a dynamic interplay between BRCA2 and the WRN DNA helicase/exonuclease defective in the premature aging disorder Werner syndrome. WRN and BRCA2 participate in complementary pathways to stabilize replication forks in cancer cells, allowing them to proliferate. Whether the functional overlap of WRN and BRCA2 is relevant to replication at gaps between newly synthesized DNA fragments, protection of telomeres, and/or metabolism of secondary DNA structures remain to be determined. Advances in understanding the mechanisms elicited during replication stress have prompted the community to reconsider avenues for cancer therapy. Insights from studies of PARP or topoisomerase inhibitors provide working models for the investigation of WRN's mechanism of action. We discuss these topics, focusing on the implications of the WRN-BRCA2 genetic interaction under conditions of replication stress.
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Affiliation(s)
- Arindam Datta
- Helicases and Genomic Integrity Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA
| | - Robert M Brosh
- Helicases and Genomic Integrity Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA
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9
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Liu Y, Zhu X, Wang K, Zhang B, Qiu S. The Cellular Functions and Molecular Mechanisms of G-Quadruplex Unwinding Helicases in Humans. Front Mol Biosci 2021; 8:783889. [PMID: 34912850 PMCID: PMC8667583 DOI: 10.3389/fmolb.2021.783889] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 11/02/2021] [Indexed: 01/19/2023] Open
Abstract
G-quadruplexes (G4s) are stable non-canonical secondary structures formed by G-rich DNA or RNA sequences. They play various regulatory roles in many biological processes. It is commonly agreed that G4 unwinding helicases play key roles in G4 metabolism and function, and these processes are closely related to physiological and pathological processes. In recent years, more and more functional and mechanistic details of G4 helicases have been discovered; therefore, it is necessary to carefully sort out the current research efforts. Here, we provide a systematic summary of G4 unwinding helicases from the perspective of functions and molecular mechanisms. First, we provide a general introduction about helicases and G4s. Next, we comprehensively summarize G4 unfolding helicases in humans and their proposed cellular functions. Then, we review their study methods and molecular mechanisms. Finally, we share our perspective on further prospects. We believe this review will provide opportunities for researchers to reach the frontiers in the functions and molecular mechanisms of human G4 unwinding helicases.
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Affiliation(s)
- Yang Liu
- Key laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), Collaborative Innovation Center for Mountain Ecology and Agro-Bioengineering (CICMEAB), College of Life Sciences/Institute of Agro-bioengineering, Guizhou University, Guiyang, China
- College of Basic Medicine, Zunyi Medical University, Zunyi, China
- The Key Laboratory of Fermentation Engineering and Biological Pharmacy of Guizhou Province, Guizhou University, Guiyang, China
- School of Liquor and Food Engineering, Guizhou University, Guiyang, China
| | - Xinting Zhu
- College of Basic Medicine, Zunyi Medical University, Zunyi, China
| | - Kejia Wang
- Key laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), Collaborative Innovation Center for Mountain Ecology and Agro-Bioengineering (CICMEAB), College of Life Sciences/Institute of Agro-bioengineering, Guizhou University, Guiyang, China
- The Key Laboratory of Fermentation Engineering and Biological Pharmacy of Guizhou Province, Guizhou University, Guiyang, China
- School of Liquor and Food Engineering, Guizhou University, Guiyang, China
| | - Bo Zhang
- College of Basic Medicine, Zunyi Medical University, Zunyi, China
| | - Shuyi Qiu
- Key laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), Collaborative Innovation Center for Mountain Ecology and Agro-Bioengineering (CICMEAB), College of Life Sciences/Institute of Agro-bioengineering, Guizhou University, Guiyang, China
- The Key Laboratory of Fermentation Engineering and Biological Pharmacy of Guizhou Province, Guizhou University, Guiyang, China
- School of Liquor and Food Engineering, Guizhou University, Guiyang, China
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10
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Muhseena N K, Mathukkada S, Das SP, Laha S. The repair gene BACH1 - a potential oncogene. Oncol Rev 2021; 15:519. [PMID: 34322202 PMCID: PMC8273628 DOI: 10.4081/oncol.2021.519] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Accepted: 03/02/2021] [Indexed: 12/12/2022] Open
Abstract
BACH1 encodes for a protein that belongs to RecQ DEAH helicase family and interacts with the BRCT repeats of BRCA1. The N-terminus of BACH1 functions in DNA metabolism as DNA-dependent ATPase and helicase. The C-terminus consists of BRCT domain, which interacts with BRCA1 and this interaction is one of the major regulator of BACH1 function. BACH1 plays important roles both in phosphorylated as well as dephosphorylated state and functions in coordination with multiple signaling molecules. The active helicase property of BACH1 is maintained by its dephosphorylated state. Imbalance between these two states enhances the development and progression of the diseased condition. Currently BACH1 is known as a tumor suppressor gene based on the presence of its clinically relevant mutations in different cancers. Through this review we have justified it to be named as an oncogene. In this review, we have explained the mechanism of how BACH1 in collaboration with BRCA1 or independently regulates various pathways like cell cycle progression, DNA replication during both normal and stressed situation, recombination and repair of damaged DNA, chromatin remodeling and epigenetic modifications. Mutation and overexpression of BACH1 are significantly found in different cancer types. This review enlists the molecular players which interact with BACH1 to regulate DNA metabolic functions, thereby revealing its potential for cancer therapeutics. We have identified the most mutated functional domain of BACH1, the hot spot for tumorigenesis, justifying it as a target molecule in different cancer types for therapeutics. BACH1 has high potentials of transforming a normal cell into a tumor cell if compromised under certain circumstances. Thus, through this review, we justify BACH1 as an oncogene along with the existing role of being a tumor suppressant.
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Affiliation(s)
- Katheeja Muhseena N
- Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, India
| | - Sooraj Mathukkada
- Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, India
| | - Shankar Prasad Das
- Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, India
| | - Suparna Laha
- Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, India
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11
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Lejault P, Mitteaux J, Sperti FR, Monchaud D. How to untie G-quadruplex knots and why? Cell Chem Biol 2021; 28:436-455. [PMID: 33596431 DOI: 10.1016/j.chembiol.2021.01.015] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 12/08/2020] [Accepted: 01/20/2021] [Indexed: 12/12/2022]
Abstract
For over two decades, the prime objective of the chemical biology community studying G-quadruplexes (G4s) has been to use chemicals to interact with and stabilize G4s in cells to obtain mechanistic interpretations. This strategy has been undoubtedly successful, as demonstrated by recent advances. However, these insights have also led to a fundamental rethinking of G4-targeting strategies: due to the prevalence of G4s in the human genome, transcriptome, and ncRNAome (collectively referred to as the G4ome), and their involvement in human diseases, should we continue developing G4-stabilizing ligands or should we invest in designing molecular tools to unfold G4s? Here, we first focus on how, when, and where G4s fold in cells; then, we describe the enzymatic systems that have evolved to counteract G4 folding and how they have been used as tools to manipulate G4s in cells; finally, we present strategies currently being implemented to devise new molecular G4 unwinding agents.
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Affiliation(s)
- Pauline Lejault
- Institut de Chimie Moléculaire de l'Université de Bourgogne, ICMUB CNRS UMR 6302, UBFC Dijon, France
| | - Jérémie Mitteaux
- Institut de Chimie Moléculaire de l'Université de Bourgogne, ICMUB CNRS UMR 6302, UBFC Dijon, France
| | - Francesco Rota Sperti
- Institut de Chimie Moléculaire de l'Université de Bourgogne, ICMUB CNRS UMR 6302, UBFC Dijon, France
| | - David Monchaud
- Institut de Chimie Moléculaire de l'Université de Bourgogne, ICMUB CNRS UMR 6302, UBFC Dijon, France.
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12
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Zell J, Rota Sperti F, Britton S, Monchaud D. DNA folds threaten genetic stability and can be leveraged for chemotherapy. RSC Chem Biol 2021; 2:47-76. [PMID: 35340894 PMCID: PMC8885165 DOI: 10.1039/d0cb00151a] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 09/20/2020] [Indexed: 12/22/2022] Open
Abstract
Damaging DNA is a current and efficient strategy to fight against cancer cell proliferation. Numerous mechanisms exist to counteract DNA damage, collectively referred to as the DNA damage response (DDR) and which are commonly dysregulated in cancer cells. Precise knowledge of these mechanisms is necessary to optimise chemotherapeutic DNA targeting. New research on DDR has uncovered a series of promising therapeutic targets, proteins and nucleic acids, with application notably via an approach referred to as combination therapy or combinatorial synthetic lethality. In this review, we summarise the cornerstone discoveries which gave way to the DNA being considered as an anticancer target, and the manipulation of DDR pathways as a valuable anticancer strategy. We describe in detail the DDR signalling and repair pathways activated in response to DNA damage. We then summarise the current understanding of non-B DNA folds, such as G-quadruplexes and DNA junctions, when they are formed and why they can offer a more specific therapeutic target compared to that of canonical B-DNA. Finally, we merge these subjects to depict the new and highly promising chemotherapeutic strategy which combines enhanced-specificity DNA damaging and DDR targeting agents. This review thus highlights how chemical biology has given rise to significant scientific advances thanks to resolutely multidisciplinary research efforts combining molecular and cell biology, chemistry and biophysics. We aim to provide the non-specialist reader a gateway into this exciting field and the specialist reader with a new perspective on the latest results achieved and strategies devised.
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Affiliation(s)
- Joanna Zell
- Institut de Chimie Moléculaire de l'Université de Bourgogne, ICMUB CNRS UMR 6302, UBFC Dijon France
| | - Francesco Rota Sperti
- Institut de Chimie Moléculaire de l'Université de Bourgogne, ICMUB CNRS UMR 6302, UBFC Dijon France
| | - Sébastien Britton
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS Toulouse France
- Équipe Labellisée la Ligue Contre le Cancer 2018 Toulouse France
| | - David Monchaud
- Institut de Chimie Moléculaire de l'Université de Bourgogne, ICMUB CNRS UMR 6302, UBFC Dijon France
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13
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Awate S, Sommers JA, Datta A, Nayak S, Bellani MA, Yang O, Dunn CA, Nicolae CM, Moldovan GL, Seidman MM, Cantor SB, Brosh RM. FANCJ compensates for RAP80 deficiency and suppresses genomic instability induced by interstrand cross-links. Nucleic Acids Res 2020; 48:9161-9180. [PMID: 32797166 DOI: 10.1093/nar/gkaa660] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 07/24/2020] [Accepted: 07/28/2020] [Indexed: 12/16/2022] Open
Abstract
FANCJ, a DNA helicase and interacting partner of the tumor suppressor BRCA1, is crucial for the repair of DNA interstrand crosslinks (ICL), a highly toxic lesion that leads to chromosomal instability and perturbs normal transcription. In diploid cells, FANCJ is believed to operate in homologous recombination (HR) repair of DNA double-strand breaks (DSB); however, its precise role and molecular mechanism is poorly understood. Moreover, compensatory mechanisms of ICL resistance when FANCJ is deficient have not been explored. In this work, we conducted a siRNA screen to identify genes of the DNA damage response/DNA repair regime that when acutely depleted sensitize FANCJ CRISPR knockout cells to a low concentration of the DNA cross-linking agent mitomycin C (MMC). One of the top hits from the screen was RAP80, a protein that recruits repair machinery to broken DNA ends and regulates DNA end-processing. Concomitant loss of FANCJ and RAP80 not only accentuates DNA damage levels in human cells but also adversely affects the cell cycle checkpoint, resulting in profound chromosomal instability. Genetic complementation experiments demonstrated that both FANCJ's catalytic activity and interaction with BRCA1 are important for ICL resistance when RAP80 is deficient. The elevated RPA and RAD51 foci in cells co-deficient of FANCJ and RAP80 exposed to MMC are attributed to single-stranded DNA created by Mre11 and CtIP nucleases. Altogether, our cell-based findings together with biochemical studies suggest a critical function of FANCJ to suppress incompletely processed and toxic joint DNA molecules during repair of ICL-induced DNA damage.
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Affiliation(s)
- Sanket Awate
- Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD, USA
| | - Joshua A Sommers
- Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD, USA
| | - Arindam Datta
- Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD, USA
| | - Sumeet Nayak
- Department of Cancer Biology, University of Massachusetts Medical School - UMASS Memorial Cancer Center, Worcester, MA, USA
| | - Marina A Bellani
- Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD, USA
| | - Olivia Yang
- Department of Biophysics and Biophysical Chemistry, Johns Hopkins University, Baltimore, MD, USA
| | - Christopher A Dunn
- Flow Cytometry Unit, National Institute on Aging, NIH, Baltimore, MD, USA
| | - Claudia M Nicolae
- Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA, USA
| | - George-Lucian Moldovan
- Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA, USA
| | - Michael M Seidman
- Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD, USA
| | - Sharon B Cantor
- Department of Cancer Biology, University of Massachusetts Medical School - UMASS Memorial Cancer Center, Worcester, MA, USA
| | - Robert M Brosh
- Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD, USA
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14
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Dhar S, Datta A, Brosh RM. DNA helicases and their roles in cancer. DNA Repair (Amst) 2020; 96:102994. [PMID: 33137625 DOI: 10.1016/j.dnarep.2020.102994] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 09/28/2020] [Indexed: 12/15/2022]
Abstract
DNA helicases, known for their fundamentally important roles in genomic stability, are high profile players in cancer. Not only are there monogenic helicase disorders with a strong disposition to cancer, it is well appreciated that helicase variants are associated with specific cancers (e.g., breast cancer). Flipping the coin, DNA helicases are frequently overexpressed in cancerous tissues and reduction in helicase gene expression results in reduced proliferation and growth capacity, as well as DNA damage induction and apoptosis of cancer cells. The seminal roles of helicases in the DNA damage and replication stress responses, as well as DNA repair pathways, validate their vital importance in cancer biology and suggest their potential values as targets in anti-cancer therapy. In recent years, many laboratories have characterized the specialized roles of helicase to resolve transcription-replication conflicts, maintain telomeres, mediate cell cycle checkpoints, remodel stalled replication forks, and regulate transcription. In vivo models, particularly mice, have been used to interrogate helicase function and serve as a bridge for preclinical studies that may lead to novel therapeutic approaches. In this review, we will summarize our current knowledge of DNA helicases and their roles in cancer, emphasizing the latest developments.
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Affiliation(s)
- Srijita Dhar
- Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Arindam Datta
- Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Robert M Brosh
- Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
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15
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Mutations in conserved functional domains of human RecQ helicases are associated with diseases and cancer: A review. Biophys Chem 2020; 265:106433. [DOI: 10.1016/j.bpc.2020.106433] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/06/2020] [Accepted: 07/11/2020] [Indexed: 12/12/2022]
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16
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Hazeslip L, Zafar MK, Chauhan MZ, Byrd AK. Genome Maintenance by DNA Helicase B. Genes (Basel) 2020; 11:E578. [PMID: 32455610 PMCID: PMC7290933 DOI: 10.3390/genes11050578] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 05/18/2020] [Accepted: 05/19/2020] [Indexed: 12/25/2022] Open
Abstract
DNA Helicase B (HELB) is a conserved helicase in higher eukaryotes with roles in the initiation of DNA replication and in the DNA damage and replication stress responses. HELB is a predominately nuclear protein in G1 phase where it is involved in initiation of DNA replication through interactions with DNA topoisomerase 2-binding protein 1 (TOPBP1), cell division control protein 45 (CDC45), and DNA polymerase α-primase. HELB also inhibits homologous recombination by reducing long-range end resection. After phosphorylation by cyclin-dependent kinase 2 (CDK2) at the G1 to S transition, HELB is predominately localized to the cytosol. However, this cytosolic localization in S phase is not exclusive. HELB has been reported to localize to chromatin in response to replication stress and to localize to the common fragile sites 16D (FRA16D) and 3B (FRA3B) and the rare fragile site XA (FRAXA) in S phase. In addition, HELB is phosphorylated in response to ionizing radiation and has been shown to localize to chromatin in response to various types of DNA damage, suggesting it has a role in the DNA damage response.
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Affiliation(s)
- Lindsey Hazeslip
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (L.H.); (M.K.Z.); (M.Z.C.)
| | - Maroof Khan Zafar
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (L.H.); (M.K.Z.); (M.Z.C.)
| | - Muhammad Zain Chauhan
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (L.H.); (M.K.Z.); (M.Z.C.)
| | - Alicia K. Byrd
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (L.H.); (M.K.Z.); (M.Z.C.)
- Winthrop P. Rockefeller Cancer Institute, Little Rock, AR 72205, USA
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17
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Voutsadakis IA. Landscape of BRIP1 molecular lesions in gastrointestinal cancers from published genomic studies. World J Gastroenterol 2020; 26:1197-1207. [PMID: 32231423 PMCID: PMC7093310 DOI: 10.3748/wjg.v26.i11.1197] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 02/21/2020] [Accepted: 03/05/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND BRIP1 is a helicase that partners with BRCA1 in the homologous recombination (HR) step in the repair of DNA inter-strand cross-link lesions. It is a rare cause of hereditary ovarian cancer in patients with no mutations of BRCA1 or BRCA2. The role of the protein in other cancers such as gastrointestinal (GI) carcinomas is less well characterized but given its role in DNA repair it could be a candidate tumor suppressor similarly to the two BRCA proteins.
AIM To analyze the role of helicase BRIP1 (FANCJ) in GI cancers pathogenesis.
METHODS Publicly available data from genomic studies of esophageal, gastric, pancreatic, cholangiocarcinomas and colorectal cancers were interrogated to unveil the role of BRIP1 in these carcinomas and to discover associations of lesions in BRIP1 with other more common molecular defects in these cancers.
RESULTS Molecular lesions in BRIP1 were rare (3.6% of all samples) in GI cancers and consisted almost exclusively of mutations and amplifications. Among mutations, 40% were possibly pathogenic according to the OncoKB database. A majority of BRIP1 mutated GI cancers were hyper-mutated due to concomitant mutations in mismatch repair or polymerase ε and δ1 genes. No associations were discovered between amplifications of BRIP1 and any mutated genes. In gastroesophageal cancers BRIP1 amplification commonly co-occurs with ERBB2 amplification.
CONCLUSION Overall BRIP1 molecular defects do not seem to play a major role in GI cancers whereas mutations frequently occur in hypermutated carcinomas and co-occur with other HR genes mutations. Despite their rarity, BRIP1 defects may present an opportunity for therapeutic interventions similar to other HR defects.
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Affiliation(s)
- Ioannis A Voutsadakis
- Algoma District Cancer Program, Sault Area Hospital, Sault Ste Marie, ON P6B 0A8, Canada
- Section of Internal Medicine, Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, ON P0M 2Z0, Canada
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18
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Brosh RM, Matson SW. History of DNA Helicases. Genes (Basel) 2020; 11:genes11030255. [PMID: 32120966 PMCID: PMC7140857 DOI: 10.3390/genes11030255] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 02/18/2020] [Accepted: 02/20/2020] [Indexed: 12/13/2022] Open
Abstract
Since the discovery of the DNA double helix, there has been a fascination in understanding the molecular mechanisms and cellular processes that account for: (i) the transmission of genetic information from one generation to the next and (ii) the remarkable stability of the genome. Nucleic acid biologists have endeavored to unravel the mysteries of DNA not only to understand the processes of DNA replication, repair, recombination, and transcription but to also characterize the underlying basis of genetic diseases characterized by chromosomal instability. Perhaps unexpectedly at first, DNA helicases have arisen as a key class of enzymes to study in this latter capacity. From the first discovery of ATP-dependent DNA unwinding enzymes in the mid 1970's to the burgeoning of helicase-dependent pathways found to be prevalent in all kingdoms of life, the story of scientific discovery in helicase research is rich and informative. Over four decades after their discovery, we take this opportunity to provide a history of DNA helicases. No doubt, many chapters are left to be written. Nonetheless, at this juncture we are privileged to share our perspective on the DNA helicase field - where it has been, its current state, and where it is headed.
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Affiliation(s)
- Robert M. Brosh
- Section on DNA Helicases, Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
- Correspondence: (R.M.B.J.); (S.W.M.); Tel.: +1-410-558-8578 (R.M.B.J.); +1-919-962-0005 (S.W.M.)
| | - Steven W. Matson
- Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Correspondence: (R.M.B.J.); (S.W.M.); Tel.: +1-410-558-8578 (R.M.B.J.); +1-919-962-0005 (S.W.M.)
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19
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Datta A, Brosh RM. Holding All the Cards-How Fanconi Anemia Proteins Deal with Replication Stress and Preserve Genomic Stability. Genes (Basel) 2019; 10:genes10020170. [PMID: 30813363 PMCID: PMC6409899 DOI: 10.3390/genes10020170] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 02/14/2019] [Accepted: 02/15/2019] [Indexed: 12/18/2022] Open
Abstract
Fanconi anemia (FA) is a hereditary chromosomal instability disorder often displaying congenital abnormalities and characterized by a predisposition to progressive bone marrow failure (BMF) and cancer. Over the last 25 years since the discovery of the first linkage of genetic mutations to FA, its molecular genetic landscape has expanded tremendously as it became apparent that FA is a disease characterized by a defect in a specific DNA repair pathway responsible for the correction of covalent cross-links between the two complementary strands of the DNA double helix. This pathway has become increasingly complex, with the discovery of now over 20 FA-linked genes implicated in interstrand cross-link (ICL) repair. Moreover, gene products known to be involved in double-strand break (DSB) repair, mismatch repair (MMR), and nucleotide excision repair (NER) play roles in the ICL response and repair of associated DNA damage. While ICL repair is predominantly coupled with DNA replication, it also can occur in non-replicating cells. DNA damage accumulation and hematopoietic stem cell failure are thought to contribute to the increased inflammation and oxidative stress prevalent in FA. Adding to its confounding nature, certain FA gene products are also engaged in the response to replication stress, caused endogenously or by agents other than ICL-inducing drugs. In this review, we discuss the mechanistic aspects of the FA pathway and the molecular defects leading to elevated replication stress believed to underlie the cellular phenotypes and clinical features of FA.
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Affiliation(s)
- Arindam Datta
- Laboratory of Molecular Gerontology, National Institute on Aging, NIH, NIH Biomedical Research Center, Baltimore, MD 21224, USA.
| | - Robert M Brosh
- Laboratory of Molecular Gerontology, National Institute on Aging, NIH, NIH Biomedical Research Center, Baltimore, MD 21224, USA.
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20
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Awate S, Dhar S, Sommers JA, Brosh RM. Cellular Assays to Study the Functional Importance of Human DNA Repair Helicases. Methods Mol Biol 2019; 1999:185-207. [PMID: 31127577 PMCID: PMC9123881 DOI: 10.1007/978-1-4939-9500-4_11] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
DNA helicases represent a specialized class of enzymes that play crucial roles in the DNA damage response. Using the energy of nucleoside triphosphate binding and hydrolysis, helicases behave as molecular motors capable of efficiently disrupting the many noncovalent hydrogen bonds that stabilize DNA molecules with secondary structure. In addition to their importance in DNA damage sensing and signaling, DNA helicases facilitate specific steps in DNA repair mechanisms that require polynucleotide tract unwinding or resolution. Because they play fundamental roles in the DNA damage response and DNA repair, defects in helicases disrupt cellular homeostasis. Thus, helicase deficiency or inhibition may result in reduced cell proliferation and survival, apoptosis, DNA damage induction, defective localization of repair proteins to sites of genomic DNA damage, chromosomal instability, and defective DNA repair pathways such as homologous recombination of double-strand breaks. In this chapter, we will describe step-by-step protocols to assay the functional importance of human DNA repair helicases in genome stability and cellular homeostasis.
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Affiliation(s)
- Sanket Awate
- Laboratory of Molecular Gerontology, National Institute on Aging, NIH, NIH Biomedical Research Center, Baltimore, MD, USA
| | - Srijita Dhar
- Laboratory of Molecular Gerontology, National Institute on Aging, NIH, NIH Biomedical Research Center, Baltimore, MD, USA
| | - Joshua A Sommers
- Laboratory of Molecular Gerontology, National Institute on Aging, NIH, NIH Biomedical Research Center, Baltimore, MD, USA
| | - Robert M Brosh
- Laboratory of Molecular Gerontology, National Institute on Aging, NIH, NIH Biomedical Research Center, Baltimore, MD, USA.
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21
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Datta A, Brosh RM. New Insights Into DNA Helicases as Druggable Targets for Cancer Therapy. Front Mol Biosci 2018; 5:59. [PMID: 29998112 PMCID: PMC6028597 DOI: 10.3389/fmolb.2018.00059] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 06/06/2018] [Indexed: 12/28/2022] Open
Abstract
Small molecules that deter the functions of DNA damage response machinery are postulated to be useful for enhancing the DNA damaging effects of chemotherapy or ionizing radiation treatments to combat cancer by impairing the proliferative capacity of rapidly dividing cells that accumulate replicative lesions. Chemically induced or genetic synthetic lethality is a promising area in personalized medicine, but it remains to be optimized. A new target in cancer therapy is DNA unwinding enzymes known as helicases. Helicases play critical roles in all aspects of nucleic acid metabolism. We and others have investigated small molecule targeted inhibition of helicase function by compound screens using biochemical and cell-based approaches. Small molecule-induced trapping of DNA helicases may represent a generalized mechanism exemplified by certain topoisomerase and PARP inhibitors that exert poisonous consequences, especially in rapidly dividing cancer cells. Taking the lead from the broader field of DNA repair inhibitors and new information gleaned from structural and biochemical studies of DNA helicases, we predict that an emerging strategy to identify useful helicase-interacting compounds will be structure-based molecular docking interfaced with a computational approach. Potency, specificity, drug resistance, and bioavailability of helicase inhibitor drugs and targeting such compounds to subcellular compartments where the respective helicases operate must be addressed. Beyond cancer therapy, continued and new developments in this area may lead to the discovery of helicase-interacting compounds that chemically rescue clinically relevant helicase missense mutant proteins or activate the catalytic function of wild-type DNA helicases, which may have novel therapeutic application.
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Affiliation(s)
- Arindam Datta
- Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, NIH Biomedical Research Center, Baltimore, MD, United States
| | - Robert M Brosh
- Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, NIH Biomedical Research Center, Baltimore, MD, United States
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