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

Pascal Drané, Marie Eve Brault, Gaofeng Cui, Khyati Meghani, Shweta Chaubey, Alexandre Detappe, Nishita Parnandi, Yizhou He, Xiao Feng Zheng, Maria Victoria Botuyan, Alkmini Kalousi, William T. Yewdell, Christian Münch, J. Wade Harper, Jayanta Chaudhuri, Evi Soutoglou, Georges Mer, Dipanjan Chowdhury

Research output: Contribution to journalArticle

40 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)211-216
Number of pages6
JournalNature
Volume543
Issue number7644
DOIs
StatePublished - Mar 9 2017

ASJC Scopus subject areas

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    Drané, P., Brault, M. E., Cui, G., Meghani, K., Chaubey, S., Detappe, A., Parnandi, N., He, Y., Zheng, X. F., Botuyan, M. V., Kalousi, A., Yewdell, W. T., Münch, C., Harper, J. W., Chaudhuri, J., Soutoglou, E., Mer, G., & Chowdhury, D. (2017). TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. Nature, 543(7644), 211-216. https://doi.org/10.1038/nature21358