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DNA end-resection in highly accessible chromatin produces a toxic break

By Jeroen van den Berg, Stacey E.P. Joosten, YongSoo Kim, Anna G. Manj├│n, Lenno Krenning, Lisa Koob, Femke M. Feringa, Rob Klompmaker, Bram van den Broek, Kees Jalink, Wilbert Zwart, Rene Medema

Posted 03 Jul 2019
bioRxiv DOI: 10.1101/691857

Of all damage occurring to DNA, the double strand break (DSB) is the most toxic lesion. Luckily, cells have developed multiple repair pathways to cope with these lesions. These different pathways compete for the same break, and the location of the break can influence this competition. However, the exact contribution of break location in repair pathway preference is not fully understood. We observe that most breaks prefer classical non-homologous end-joining, whereas some depend on DNA end-resection for their repair. Surprisingly, we find that for a subset of these sites, the activation of resection-dependent repair induces a detrimental DNA damage response. These sites exhibit extensive DNA end-resection due to improper recruitment of 53BP1 and the Shieldin complex due to low levels of H4K20me2. Most of these sites reside in close proximity to DNAseI hypersensitive sites. Compacting or removing these regions reduces extensive DNA end-resection and restores normal repair. Taken together, we found that DSB in open chromatin is highly toxic, due to the improper activity of 53BP1 and Shieldin, resulting in extensive DNA end-resection.

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