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

Nishita Parnandi; Veronica Rendo; Gaofeng Cui; Maria Victoria Botuyan; Michaela Remisova; Huy Nguyen; Pascal Drané; Rameen Beroukhim; Matthias Altmeyer; Georges Mer; Dipanjan Chowdhury

doi:10.1016/j.molcel.2021.03.039

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

Mol Cell. 2021 Jun 17;81(12):2583-2595.e6. doi: 10.1016/j.molcel.2021.03.039. Epub 2021 May 6.

Authors

Affiliations

¹ Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
² Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Cancer Program, Broad Institute, 415 Main Street, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
³ Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
⁴ Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland.
⁵ Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
⁶ Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: dipanjan_chowdhury@dfci.harvard.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Binding Sites
Carrier Proteins / metabolism
Cell Line, Tumor
Cell Lineage / genetics*
Cell Lineage / physiology
DNA / genetics
DNA Breaks, Double-Stranded
DNA Repair
Histones / metabolism
Humans
Protein Binding
RNA-Binding Proteins / metabolism*
RNA-Binding Proteins / physiology
Tudor Domain
Tumor Suppressor Protein p53 / metabolism
Tumor Suppressor p53-Binding Protein 1 / metabolism*
Tumor Suppressor p53-Binding Protein 1 / physiology

Substances

Carrier Proteins
Histones
NUDT16L1 protein, human
RNA-Binding Proteins
TP53BP1 protein, human
Tumor Suppressor Protein p53
Tumor Suppressor p53-Binding Protein 1
DNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding