Table 1.

Predominant DNA repair pathways

Double-strand break repair pathways
Classic (c)-NHEJ
  • Predominant DNA DSB repair pathway in human cells, functioning throughout the cell cycle.

  • Involves the relatively rapid ligation of broken DNA ends, mediated by the core NHEJ complex, including DNA-PK, XRCC4, LIG4, XLF, and PAXX, amongst others.

  • DNA end processing and DNA polymerase action may be required before ligation can occur, making NHEJ inherently error prone.

  • NHEJ maintains genome stability, however, by rapidly repairing DSBs in circumstances where recombinogenic events would likely result in gross chromosomal rearrangements; in noncycling or G1 cells, for example (38, 39).

Homology-directed repair
Homologous recombination (HR)
  • Relatively slow and restricted to late-S phase/G2, as it generally relies on a homologous sister chromatid DNA strand for repair.

  • Extensive DNA end resection by helicases and exonucleases, such as DNA2, BLM, WRN, and EXO1, results in a 3′–ssDNA overhang, committing the break to repair by HR.

  • Replication protein A (RPA) coats and stabilizes the ssDNA, leading to ATR activation and subsequent signaling events.

  • BRCA2, with the help of BRCA1 and PALB2, loads RAD51 onto the RPA-coated ssDNA, leading to strand invasion, with a number of factors negatively regulating this process to prevent hyper-recombination such as POLQ, PARI, RECQL5, FANCJ, and BLM (151).

Alternative (Alt)-NHEJ or MMEJ
  • Ligation pathway for DSBs when c-NHEJ is genetically compromised (152).

  • Occurs following limited DNA end resection.

  • Contributes to the excessive genomic deletions and chromosomal translocations seen in tumors and may also provide a back-up repair pathway in HR-deficient cells (10, 20).

Single-strand annealing (SSA)
  • Mutagenic, RAD51-independent repair pathway, involving annealing of short or longer complimentary DNA sequences on resected DNA with subsequent deletion of the intervening DNA sequence. The detailed mechanism has yet to be defined in mammalian cells (20).

Other repair pathways
Interstrand cross-link (ICL) repair
  • ICLs cause DNA replication fork stalling and collapse, resulting in DNA DSBs.

  • ICLs are recognized by the FANCONI core complex, which engages HR, TLS, and NER pathways to repair the DNA lesion (153).

SSB repair
  • SSBs usually arise following the removal of a damaged nucleotide (154).

  • PARP1 is the DNA-damage sensor protein for DNA strand breaks. PARP1 localizes to sites of DNA damage, generating extensive PAR (poly ADP-ribose) chains.

  • Ribosylated PARP1 promotes recruitment of SSB-repair proteins to DNA-damage sites (9).

  • DNA glycosylases recognize and remove damaged bases leading to basic sites that are processed by APE1.

  • Results in SSB generation, repaired using SSB repair pathways (86).

Translesion synthesis (TLS)
  • DNA damage tolerance pathway that helps prevent replication fork stalling (155).

  • Engages low-fidelity DNA Y-family polymerases (e.g., REV1, POLH, POLI, and POLK) that accommodate the damaged lesion, replicating past it, at the expense of increased mutagenesis.

Nucleotide excision repair (NER)
  • Removes helix-distorting lesions from DNA, in particular the UV-induced photo lesions.

  • Involves removal of a short oligonucleotide, including the damaged lesion using structure-specific endonucleases and subsequent restoration of the DNA sequence by DNA polymerases (156).

Mismatch repair (MMR)
  • MSH2, MSH3, and MSH6 recognize base–base mismatches and insertion/deletion loops, where they recruit MLH1 and PMS2 to damaged sites. The concerted actions of the MMR proteins engage EXO1 to remove the mismatch and then POLD and LIG1 to fill the gap and seal the nick, respectively (157).