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Alternative end-joining mechanisms: a historical perspective
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, unusu...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2013
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613618/ https://www.ncbi.nlm.nih.gov/pubmed/23565119 http://dx.doi.org/10.3389/fgene.2013.00048 |
Sumario: | 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. |
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