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Review
. 2022 Mar 1;36(5-6):278-293.
doi: 10.1101/gad.349431.122.

DNA repair defects in cancer and therapeutic opportunities

Jessica L Hopkins  1 , Li Lan  1   2 , Lee Zou  1   3
Affiliations
Review

DNA repair defects in cancer and therapeutic opportunities

Jessica L Hopkins et al. Genes Dev. .

Abstract

DNA repair and DNA damage signaling pathways are critical for the maintenance of genomic stability. Defects of DNA repair and damage signaling contribute to tumorigenesis, but also render cancer cells vulnerable to DNA damage and reliant on remaining repair and signaling activities. Here, we review the major classes of DNA repair and damage signaling defects in cancer, the genomic instability that they give rise to, and therapeutic strategies to exploit the resulting vulnerabilities. Furthermore, we discuss the impacts of DNA repair defects on both targeted therapy and immunotherapy, and highlight emerging principles for targeting DNA repair defects in cancer therapy.

Keywords: ATM; ATR; BRCA; DNA damage; DNA repair; PARP; cancer; genomic instability; immunotherapy; targeted therapy.

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Figures

Figure 1.
Figure 1.
Functions of BRCA1/2 in homologous recombination. The BRCA1–BARD1 complex is recruited to the DSB-flanking chromatin marked by H2A K15ub and H4 K20me0 (Becker et al. 2021; Hu et al. 2021). The BRCA1 at DSBs recruits PALB2–BRCA2 to promote the assembly of RAD51 filaments, which enables D-loop formation following the resection by MRE11-CtIP and EXO1 or MRE11-CtIP and DNA2.
Figure 2.
Figure 2.
Functions of BRCA1/2 in protecting replication forks. In BRCA1/2-proficient cells, reversed replication forks are protected from nucleolytic degradation by RAD51 in a BRCA1/2-dependent manner. In BRCA1/2-deficient cells, nascent DNA at reversed forks is increasingly degraded. Degradation of nascent DNA in BRCA2-deficient cells leads to MUS81- and POLD3-dependent, error-prone fork restart. Furthermore, ssDNA gaps accumulate during replication in BRCA1/2-deficient cells. BRCA1-deficient cells are defective for protecting ssDNA gaps against the MRE11 nuclease, reducing TS- and TLS-mediated gap repair.
Figure 3.
Figure 3.
Models for the selective killing of BRCA1/2-deficient cells by PARPi. (A) PARPi induces more ssDNA gaps in BRCA1/2-deficient cells, promoting RPA exhaustion and replication catastrophe. (B) PARPi induces ssDNA gaps during replication and prevents complete gap repair, allowing gaps to persist into the next cell cycle and generate DSBs upon collisions with replication forks. BRCA1/2-deficient cells fail to repair collapsed forks and mount a checkpoint response, leading to progressive accumulation of DSBs over multiple cell cycles and cell death.
Figure 4.
Figure 4.
Selective killing of BRCA1/2-deficient cells by different DDR targeted drugs. Both PARPi and REV1i render the ssDNA gaps in BRCA1/2-deficient cells persistent, promoting DSBs or replication catastrophe. POLθi blocks MMEJ and prevents alternative repair of DSBs in HR-defective cells, rendering DSBs persistent in BRCA1/2-deficient cells.
See this image and copyright information in PMC

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