4.3 Article

Sp1-dependent recruitment of the histone acetylase p300 to DSBs facilitates chromatin remodeling and recruitment of the NHEJ repair factor Ku70

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DNA REPAIR
卷 105, 期 -, 页码 -

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ELSEVIER
DOI: 10.1016/j.dnarep.2021.103171

关键词

DNA damage; Double strand break repair; NHEJ; Sp1; p300

资金

  1. Drexel University College of Medicine Aging Initiative Graduate Student Fellowship

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This study demonstrates the importance of Sp1 phosphorylation by ATM in facilitating the interaction with p300 for DSB repair. The recruitment of p300 to DSBs by Sp1 is essential for modifying histones and recruiting repair factors. Depletion of Sp1 leads to defects in histone acetylation and recruitment of repair proteins, highlighting the critical role of Sp1 in regulating chromatin remodelers for proper DSB repair.
In response to DNA damage, most factors involved in damage recognition and repair are tightly regulated to ensure proper repair pathway choice. Histone acetylation at DNA double strand breaks (DSBs) by p300 histone acetyltransferase (HAT) is critical for the recruitment of DSB repair proteins to chromatin. Here, we show that phosphorylation of Sp1 by ATM increases its interaction with p300 and that Sp1-dependent recruitment of p300 to DSBs is necessary to modify the histones associated with p300 activity and NHEJ repair factor recruitment and repair. p300 is known to acetylate multiple residues on histones H3 and H4 necessary for NHEJ. Acetylation of H3K18 by p300 is associated with the recruitment of the SWI/SNF chromatin remodeling complex and Ku70 to DSBs for NHEJ repair. Depletion of Sp1 results in decreased acetylation of lysines on histones H3 and H4. Specifically, cells depleted of Sp1 display defects in the acetylation of H3K18, resulting in defective SWI/SNF and Ku70 recruitment to DSBs. These results shed light on mechanisms by which chromatin remodelers are regulated to ensure activation of the appropriate DSB repair pathway.

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