title: TIRR regulates 53BP1 by masking its histone methyl-lysine binding function.
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.
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Pascal
authors.initials: P
authors.lastname: Drané
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Brault
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Cui
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Khyati
authors.initials: K
authors.lastname: Meghani
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Shweta
authors.initials: S
authors.lastname: Chaubey
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Detappe
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Nishita
authors.initials: N
authors.lastname: Parnandi
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Yizhou
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Zheng
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Maria Victoria
authors.initials: MV
authors.lastname: Botuyan
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch 67404, France.
authors.forename: Alkmini
authors.initials: A
authors.lastname: Kalousi
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, Gerstner Sloan-Kettering Graduate School, New York, New York 10065, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Yewdell
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Münch
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: J Wade
authors.initials: JW
authors.lastname: Harper
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, Gerstner Sloan-Kettering Graduate School, New York, New York 10065, USA.|Immunology and Microbial Pathogenesis Program, Weill-Cornell Medical School, New York, New York 10065, USA.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Chaudhuri
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch 67404, France.
authors.forename: Evi
authors.initials: E
authors.lastname: Soutoglou
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Georges
authors.initials: G
authors.lastname: Mer
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.|Department of Biological Chemistry &Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Dipanjan
authors.initials: D
authors.lastname: Chowdhury
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D005260:Female; D006657:Histones / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011485:Protein Binding; D000072417:Protein Domains; D016601:RNA-Binding Proteins; D034501:Telomere-Binding Proteins / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D006657:Histones; C000621267:NUDT16L1 protein, human; D016601:RNA-Binding Proteins; C492743:Rif1 protein, human; C498301:TP53BP1 protein, human; D034501:Telomere-Binding Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D008239:Lysine