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TIRR regulates 53BP1 by masking its histone methyl-lysine binding function
journal contribution
posted on 2023-06-07, 07:25 authored by 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 SoutoglouEvi Soutoglou, Georges Mer, Dipanjan Chowdhury53BP1 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.
History
Publication status
- Published
File Version
- Accepted version
Journal
NatureISSN
0028-0836Publisher
Nature ResearchExternal DOI
Volume
543Page range
211-216Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2020-07-06First Open Access (FOA) Date
2020-07-06First Compliant Deposit (FCD) Date
2020-07-06Usage metrics
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