期刊
NUCLEIC ACIDS RESEARCH
卷 48, 期 4, 页码 1905-1924出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkz1167
关键词
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资金
- Bundesministerium fur Bildung und Forschung, BMBF (Federal Ministry of Education and Research) [02S8254, 02S8467, 03NUK005C, 02NUK043B]
- Deutsche Forschungsgemeinschaft, DFG [GRK1739, IL51-11-1]
- BMBF
In vertebrates, genomic DNA double-strand breaks (DSBs) are removed by non-homologous end-joining processes: classical non-homologous end-joining (c-NHEJ) and alternative end-joining (alt-EJ); or by homology-dependent processes: gene-conversion (GC) and single-strand annealing (SSA). Surprisingly, these repair pathways are not real alternative options restoring genome integrity with equal efficiency, but show instead striking differences in speed, accuracy and cell-cycle-phase dependence. As a consequence, engagement of one pathway may be associated with processing-risks for the genome absent from another pathway. Characterization of engagement-parameters and their consequences is, therefore, essential for understanding effects on the genome of DSB-inducing agents, such as ionizin-gradiation (IR). Here, by addressing pathway selection in G(2)-phase, we discover regulatory confinements in GC with consequences for SSA- and c-NHEJ-engagement. We show pronounced suppression of GC with increasing DSB-load that is not due to RAD51 availability and which is delimited but not defined by 53BP1 and RAD52. Strikingly, at low DSB-loads, GC repairs similar to 50% of DSBs, whereas at high DSB-loads its contribution is undetectable. Notably, with increasing DSB-load and the associated suppression of GC, SSA gains ground, while alt-EJ is suppressed. These observations explain earlier, apparently contradictory results and advance our understanding of logic and mechanisms underpinning the wiring between DSB repair pathways.
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