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

Drané, Pascal, Brault, Marie-Eve, Cui, Gaofeng, Meghani, Khyati, Chaubey, Shweta, Detappe, Alexandre, Parnandi, Nishita, He, Yizhou, Zheng, Xiao-Feng, Botuyan, Maria Victoria, Kalousi, Alkmini, Yewdell, William T, Münch, Christian, Harper, J Wade, Chaudhuri, Jayanta, Soutoglou, Evi, Mer, Georges and Chowdhury, Dipanjan (2017) TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. Nature, 543. pp. 211-216. ISSN 0028-0836

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53BP1 is a multi-functional double-strand break (DSB) repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumors to PARP inhibitors. Central to all 53BP1 activities is its recruitment to DSBs via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, TIRR (Tudor Interacting Repair Regulator) that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, ATM phosphorylates 53BP1 and recruits RIF1 to dissociate the 53BP1–TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to DSBs. Depletion of TIRR destabilizes 53BP1 in the nuclear soluble fraction and also alters the DSB-induced protein complex centering 53BP1. These findings identify TIRR as a new factor that influences DSB repair utilizing a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 06 Jul 2020 09:33
Last Modified: 06 Jul 2020 09:45
URI: http://sro.sussex.ac.uk/id/eprint/92310

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