Microhomology-mediated end joining: Good, bad and ugly

Mutat Res. 2018 May;809:81-87. doi: 10.1016/j.mrfmmm.2017.07.002. Epub 2017 Jul 16.


DNA double-strand breaks (DSBs) are induced by a variety of genotoxic agents, including ionizing radiation and chemotherapy drugs for treating cancers. The elimination of DSBs proceeds via distinctive error-free and error-prone pathways. Repair by homologous recombination (HR) is largely error-free and mediated by RAD51/BRCA2 gene products. Classical non-homologous end joining (C-NHEJ) requires the Ku heterodimer and can efficiently rejoin breaks, with occasional loss or gain of DNA information. Recently, evidence has unveiled another DNA end-joining mechanism that is independent of recombination factors and Ku proteins, termed alternative non-homologous end joining (A-NHEJ). While A-NHEJ-mediated repair does not require homology, in a subtype of A-NHEJ, DSB breaks are sealed by microhomology (MH)-mediated base-pairing of DNA single strands, followed by nucleolytic trimming of DNA flaps, DNA gap filling, and DNA ligation, yielding products that are always associated with DNA deletion. This highly error-prone DSB repair pathway is termed microhomology-mediated end joining (MMEJ). Dissecting the mechanisms of MMEJ is of great interest because of its potential to destabilize the genome through gene deletions and chromosomal rearrangements in cells deficient in canonical repair pathways, including HR and C-NHEJ. In addition, evidence now suggests that MMEJ plays a physiological role in normal cells.

Keywords: Chromosome rearrangement; DNA double strand break; End joining; Microhomology; Mutagenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • BRCA2 Protein / genetics
  • BRCA2 Protein / metabolism*
  • Chromosome Aberrations
  • DNA Breaks, Double-Stranded*
  • DNA End-Joining Repair*
  • Gene Deletion
  • Humans
  • Ku Autoantigen / genetics
  • Ku Autoantigen / metabolism*
  • Rad51 Recombinase / genetics
  • Rad51 Recombinase / metabolism*
  • Recombinational DNA Repair*


  • BRCA2 Protein
  • BRCA2 protein, human
  • RAD51 protein, human
  • Rad51 Recombinase
  • XRCC5 protein, human
  • Ku Autoantigen