@article{5c5275e3b158466dbf9c3acdcaa90dc8,
title = "TIRR inhibits the 53BP1-p53 complex to alter cell-fate programs",
abstract = "53BP1 influences genome stability via two independent mechanisms: (1) regulating DNA double-strand break (DSB) repair and (2) enhancing p53 activity. We discovered a protein, Tudor-interacting repair regulator (TIRR), that associates with the 53BP1 Tudor domain and prevents its recruitment to DSBs. Here, we elucidate how TIRR affects 53BP1 function beyond its recruitment to DSBs and biochemically links the two distinct roles of 53BP1. Loss of TIRR causes an aberrant increase in the gene transactivation function of p53, affecting several p53-mediated cell-fate programs. TIRR inhibits the complex formation between the Tudor domain of 53BP1 and a dimethylated form of p53 (K382me2) that is poised for transcriptional activation of its target genes. TIRR mRNA expression levels negatively correlate with the expression of key p53 target genes in breast and prostate cancers. Further, TIRR loss is selectively not tolerated in p53-proficient tumors. Therefore, we establish that TIRR is an important inhibitor of the 53BP1-p53 complex.",
keywords = "53BP1, NMR, TIRR, Tudor, cancer, cell fate, p53, senescence, survival, transcription factor",
author = "Nishita Parnandi and Veronica Rendo and Gaofeng Cui and Botuyan, {Maria Victoria} and Michaela Remisova and Huy Nguyen and Pascal Dran{\'e} and Rameen Beroukhim and Matthias Altmeyer and Georges Mer and Dipanjan Chowdhury",
note = "Funding Information: D.C. is supported by R01 CA208244, Gray Foundation Team Science Award , DOD Ovarian Cancer Award W81XWH-15-0564/OC140632 , Tina{\textquoteright}s Wish Foundation , and the Claudia Adams Barr Program in Innovative Basic Cancer Research . G.M. is supported by NIH grants R01 CA132878 and R35 GM136262 . M.V.B. acknowledges support from an OCRA Liz Tilberis Award . M.A. is supported by the Swiss National Science Foundation ( PP00P3_179057 and 310030_197003 ) and by the European Research Council (ERC) under the European Union{\textquoteright}s Horizon 2020 research and innovation program ( ERC-2016-STG 714326 ). We thank Sharmistha Pal for sharing protocols and reagents and Shrabasti Roychoudhury for comments on the manuscript. Funding Information: D.C. is supported by R01 CA208244, Gray Foundation Team Science Award, DOD Ovarian Cancer Award W81XWH-15-0564/OC140632, Tina's Wish Foundation, and the Claudia Adams Barr Program in Innovative Basic Cancer Research. G.M. is supported by NIH grants R01 CA132878 and R35 GM136262. M.V.B. acknowledges support from an OCRA Liz Tilberis Award. M.A. is supported by the Swiss National Science Foundation (PP00P3_179057 and 310030_197003) and by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (ERC-2016-STG 714326). We thank Sharmistha Pal for sharing protocols and reagents and Shrabasti Roychoudhury for comments on the manuscript. N.P. and D.C. conceived the study and wrote the paper, with input from V.R. M.V.B. H.N. M.A. G.M. and R.B. The RNA-seq data were acquired by P.D. and analyzed by H.N. The QIBC experiments were conducted and analyzed by M.R. under the supervision of M.A. The NMR and ITC experiments were conducted by G.C. and the protein purification for the same was carried out by M.V.B. under the supervision of G.M. The bioinformatic analysis was done by V.R. under the supervision of R.B. All of the other experiments were carried out by N.P. under the supervision of D.C. D.C. is a member of the Advisory Board of Molecular Cell. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = jun,
day = "17",
doi = "10.1016/j.molcel.2021.03.039",
language = "English (US)",
volume = "81",
pages = "2583--2595.e6",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "12",
}