Header

UZH-Logo

Maintenance Infos

TIRR inhibits the 53BP1-p53 complex to alter cell-fate programs


Parnandi, Nishita; Rendo, Veronica; Cui, Gaofeng; Botuyan, Maria Victoria; Remisova, Michaela; Nguyen, Huy; Drané, Pascal; Beroukhim, Rameen; Altmeyer, Matthias; Mer, Georges; Chowdhury, Dipanjan (2021). TIRR inhibits the 53BP1-p53 complex to alter cell-fate programs. Molecular Cell, 81(12):2583-2595.e6.

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.

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.

Statistics

Citations

Dimensions.ai Metrics
16 citations in Web of Science®
17 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

1 download since deposited on 02 Sep 2021
0 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Veterinärwissenschaftliches Institut > Department of Molecular Mechanisms of Disease
07 Faculty of Science > Department of Molecular Mechanisms of Disease
Dewey Decimal Classification:570 Life sciences; biology
Scopus Subject Areas:Life Sciences > Molecular Biology
Life Sciences > Cell Biology
Uncontrolled Keywords:Cell Biology, Molecular Biology
Language:English
Date:1 June 2021
Deposited On:02 Sep 2021 08:25
Last Modified:25 Jun 2024 01:43
Publisher:Cell Press (Elsevier)
ISSN:1097-2765
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.molcel.2021.03.039
Project Information:
  • : FunderNIH
  • : Grant ID
  • : Project Title