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Asymmetric Processing of DNA Ends at a Double-Strand Break Leads to Unconstrained Dynamics and Ectopic Translocation

Marcomini, Isabella and Shimada, Kenji and Delgoshaie, Neda and Yamamoto, Io and Seeber, Andrew and Cheblal, Anais and Naumann, Ulrike and Horigome, Chihiro and Gasser, Susan (2018) Asymmetric Processing of DNA Ends at a Double-Strand Break Leads to Unconstrained Dynamics and Ectopic Translocation. Cell Reports, 24 (10). 2614-2628.e4. ISSN 22111247

Abstract

Multiple pathways regulate the repair of double-strand breaks (DSBs) to suppress potentially dangerous ectopic recombination. Both sequence and chromatin context are thought to influence pathway choice between non-homologous end-joining (NHEJ) and homology-driven recombination. To test the effect of repetitive sequences on break processing, we have inserted TG-rich repeats on one side of an inducible DSB at the budding yeast MAT locus on chromosome III. Five clustered Rap1 sites within a break-proximal TG repeat are sufficient to block Mre11-Rad50-Xrs2 recruitment, impair resection, and favor elongation by telomerase. The two sides of the break lose end-to-end tethering and show enhanced, uncoordinated movement. Only the TG-free side is resected and shifts to the nuclear periphery. In contrast to persistent DSBs without TG repeats that are repaired by imprecise NHEJ, nearly all survivors of repeat-proximal DSBs repair the break by a homology-driven, non-reciprocal translocation from ChrIII-R to ChrVII-L. This suppression of imprecise NHEJ at TG-repeat-flanked DSBs requires the Uls1 translocase activity. Marcomini et al. show that the presence of interstitial telomeric repeat sequences near a double-strand break alters the outcome of repair. A TG-flanked break loads MRX asymmetrically, supports resection only on one side, and allows uncoordinated movement of the break ends. The resected TG-free end invades homology on another chromosome driving a unidirectional translocation event.

Item Type: Article
Keywords: double-strand break repair end resection homology-driven recombination imprecise non-homologous end joining interstitial repeat sequences MRX telomeres Uls1
Date Deposited: 25 Dec 2018 00:45
Last Modified: 25 Dec 2018 00:45
URI: https://oak.novartis.com/id/eprint/37109

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