In the presence of functional DNA repair pathways,
DNA double-strand breaks (DSBs) are mainly repaired by non-homologous end-joining (NHEJ) or homologous recombination (HR), two conserved pathways that protect cells from aberrant chromosomal rearrangements. During the past two decades however, unusual and presumably distinct DNA end-joining repair activities have been unraveled in NHEJ-deficient cells and these are likely to operate in various chromosomal contexts and species. Most alternative
DNA end-joining events reported so far appear to involve microhomologous sequences and are likely to rely on a subset of HR
enzymes, namely those responsible for the single-strand annealing mechanism of HR, and on
DNA Ligase III. Usually, microhomologies are not initially present at
DSB ends and thus need to be unmasked through
DNA end resection, a process that can lead to extensive
nucleotide loss and is therefore highly mutagenic. In addition to microhomology-mediated end-joining events, recent studies in mammalian cells point toward the existence of a distinct and still ill defined alternative end-joining pathway that does not appear to rely on pre-existing microhomologies and may possibly involve
DNA Ligase I. Whether dependent on microhomologies or not, alternative
DNA end-joining mechanisms are likely to be highly mutagenic in vivo, being able to drive telomere fusion events and
cancer-associated
chromosomal translocations in mouse models. In the future, it will be important to better characterize the genetic requirements of these mutagenic alternative mechanisms of
DNA end-joining.