TIRR regulates 53BP1 by masking its histone methyl-lysine binding function.

Nature
Authors
Abstract

P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.

Year of Publication
2017
Journal
Nature
Volume
543
Issue
7644
Pages
211-216
Date Published
2017 03 09
ISSN
1476-4687
DOI
10.1038/nature21358
PubMed ID
28241136
PubMed Central ID
PMC5441565
Links
Grant list
R01 GM116829 / GM / NIGMS NIH HHS / United States
P50 CA108961 / CA / NCI NIH HHS / United States
R01 CA132878 / CA / NCI NIH HHS / United States
R01 AI101897 / AI / NIAID NIH HHS / United States
R01 CA142698 / CA / NCI NIH HHS / United States
R01 AI072194 / AI / NIAID NIH HHS / United States
R01 AI124186 / AI / NIAID NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
4T32CA009149-40 / CA / NCI NIH HHS / United States