Exploiting the homologous recombination DNA repair network for targeted cancer therapy

Figure 1 DNA double strand break repair pathways. A: Homologous recombination (HR) repair. MRE11-RAD50-NBS1 (MRN) complex recognizes and senses double strand breaks (DSBs). This complex activates ATM kinase, which in turn initiates the full DNA damage response, particularly in the heterochromatin regions of chromosomes. CtIP-mediated nuclease activity is required for the end resection from 5' to 3', which leads to the formation of single-strand DNA (ssDNA). The exposed ssDNA is coated with DNA replication protein A (RPA) and activates the Ataxia Telangiectasia and Rad3-related protein (ATR) response to facilitate HR repair. Then RAD51 nucleoprotein filament is assembled, which replaces RPA-coated ssDNA, performs homology sequence searching, and mediates strand invasion. DSBs are restored by branch migration of this joint DNA molecule, DNA synthesis, ligation, and resolution of Holliday junctions; B: Non-homologous end joining (NHEJ) repair. The two broken ends are processed and ligated directly by the action of the end-binding KU70/80 complex and DNA-PKcs followed by XRCC4-ligase4.

Figure 2 The complex protein network involved in homologous recombination repair. HR: Homologous recombination; DSB: Double strand break.

Figure 3 Double strand break repair pathways and the points of action of cancer treatment drugs. HR: Homologous recombination; NHEJ: Non-homologous end joining; DSB: Double strand break; RPA: DNA replication protein A; RAD51: DNA repair protein RAD51 homolog 1; MRE11: Meiotic recombination 11 Homolog 1; NBS1: Nijmegen B breakage syndrome 1; BRCA: Breast cancer susceptibility protein; XRCC: X-ray repair cross-complementing protein.

Figure 4 Mechanism of synthetic lethality interaction between poly (ADP-ribose) polymerase inhibitors and homologous recombination repair deficiency. DSB: Double strand break; SSB: Single strand break; HR: Homologous recombination; RPA: DNA replication protein A; BRCA: Breast cancer susceptibility protein; PARP: Poly (ADP-ribose) polymerase.