Cells undergo a constant barrage of exogenous and endogenous stressors that can cause DNA damage triggering a DNA-damage response (DDR), activating a number of DNA repair pathways. DNA lesions can vary from breaks in phosphodiester bonds like single‐strand breaks (SSBs) and double‐strand breaks (DSBs) to base damage including pyrimidine dimers, mismatches, and crosslinks. If the damage is not repaired correctly, it can lead to mutations that propagate genomic instability, an underlying factor in the hallmarks of cancer promoting tumor progression. When proliferating, cancer cells become more mutagenetic and deficient in functional DNA repair pathways causing an increased susceptibility to DNA damage.
The DDR's involvement in cancer biology has led to novel targeted therapies that inhibit cancer reliant on DNA repair pathways on which cancer cells rely. For example, poly-(ADP ribose) polymerase (PARP) inhibitors have been developed for the treatment of BRCA1/2 deficient patients, which are synthetically lethal with homologous recombination (HR) repair deficient tumors. In addition, platinum-based chemotherapies generate DNA damage thereby destroying repair-deficient cancer cells.
The first line of repair of DSBs is non-homologous end joining (NHEJ), in which the broken ends are ligated without the need for a homologous template. NHEJ repair is mediated through Ku70/Ku80 heterodimer which recognizes and binds the DSBs and recruits other components including DNA-PKcs, XRCC4, LIG4, XLF and APLF. In alternative (alt)-NHEJ, PARP1 is recruited by the MRN complex, which consists of Mre11, Rad50, and Nbs1; POLQ performs the repair and XRCC1 and LIG1/3 handles ligation. Homologous recombination (HR) is a template-directed repair also for DSBs. This is a highly regulated pathway that occurs when the ends of ssDNA are degraded by endonucleases including the MRN complex. Next, the ends are coated by RPA filaments and replaced by RAD51 to locate the area of homology in the template DNA. Many tumor suppressors are involved in this pathway including BRCA1, BRCA2, and ATM.
Interstrand crosslinks (ICL) are DNA lesions caused by the covalent link between two bases from complementary strands that prevent DNA strand separation and inhibit transcription and replication. The Fanconi anemia (FA) pathway, involving Fanconi anemia complementation group (FANC) proteins, is responsible for ICL repair. SSBs involving helix-distorting bulky lesions that block DNA replication and transcription can also be corrected by nucleotide excision repair (NER). Endonucleases XPF-ERCC1 and XPG cut the damaged strands, POL δ and ε repair the damage, and LIG1 performs ligation. There are two sub pathways: the global genome (GG)-NER, which fills in the gaps formed by ssDNA due to disruption of base pairing, and transcription coupled (TC)-NER, which repairs lesion-stalled RNA polymerase II active transcription sites. Base excision repair (BER) addresses SSB base oxidation, which does not cause significant distortions of the DNA helix. BER involves chromatin remodeling at the lesion, and there are eleven different DNA glycosylases that can recognize and excise damaged bases. After excision, an abasic site is created, completing repair through either short-patch (SP) BER for single-base sites with POL β and ligation by either LIG1 or LIG3 complexed with XRCC1; or long-patch (LP) BER for oxidized and reduced sites utilizing either POL β or POL δ/ε and a LIG1-mediated ligation. DNA replication errors containing a mismatched nucleotide are repaired through the mismatch repair (MMR) pathway. Damage is recognized by either the MSH2:MSH6 or MSH2:MSH3 complexes and removed by the exonuclease EXO1.
In summary, DNA repair pathways are critical to maintain genomic stability and understanding the regulation of these mechanisms provides insights into designing strategies to target carcinogenesis and mitigate risks before cancer progresses.
