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 and Dipanjan Chowdhury ()
Additional contact information
Pascal Drané: Dana-Farber Cancer Institute
Marie-Eve Brault: Dana-Farber Cancer Institute
Gaofeng Cui: Mayo Clinic
Khyati Meghani: Dana-Farber Cancer Institute
Shweta Chaubey: Dana-Farber Cancer Institute
Alexandre Detappe: Dana-Farber Cancer Institute
Nishita Parnandi: Dana-Farber Cancer Institute
Yizhou He: Dana-Farber Cancer Institute
Xiao-Feng Zheng: Dana-Farber Cancer Institute
Maria Victoria Botuyan: Mayo Clinic
Alkmini Kalousi: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
William T. Yewdell: Immunology Program, Memorial Sloan-Kettering Cancer Center, Gerstner Sloan-Kettering Graduate School
Christian Münch: Harvard Medical School
J. Wade Harper: Harvard Medical School
Jayanta Chaudhuri: Immunology Program, Memorial Sloan-Kettering Cancer Center, Gerstner Sloan-Kettering Graduate School
Evi Soutoglou: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
Georges Mer: Mayo Clinic
Dipanjan Chowdhury: Dana-Farber Cancer Institute

Nature, 2017, vol. 543, issue 7644, 211-216

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature21358

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