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

Binding Sites Carrier Proteins / metabolism Cell Line, Tumor Cell Lineage / genetics DNA / genetics DNA Breaks, Double-Stranded DNA Repair Histones / metabolism Humans Protein Binding RNA-Binding Proteins / metabolism Tudor Domain Tumor Suppressor Protein p53 / metabolism Tumor Suppressor p53-Binding Protein 1 / metabolism
53BP1 NMR TIRR Tudor cancer cell fate p53 senescence survival transcription factor

Journal

Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571

Informations de publication

Date de publication:
17 06 2021
Historique:
received: 02 09 2020
revised: 19 01 2021
accepted: 24 03 2021
pubmed: 8 5 2021
medline: 21 7 2021
entrez: 7 5 2021
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.molcel.2021.03.039 PMID: 33961797 PMC: PMC8536467
pubmed: 33961797
pii: S1097-2765(21)00234-3
doi: 10.1016/j.molcel.2021.03.039
pmc: PMC8536467
mid: NIHMS1746068
pii:
doi:

Substances chimiques

Carrier Proteins 0
Histones 0
NUDT16L1 protein, human 0
RNA-Binding Proteins 0
TP53BP1 protein, human 0
Tumor Suppressor Protein p53 0
Tumor Suppressor p53-Binding Protein 1 0
DNA 9007-49-2

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

2583-2595.e6

Subventions

Organisme : NCI NIH HHS
ID : R01 CA132878
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA142698
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA208244
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM136262
Pays : United States

Informations de copyright

Copyright © 2021 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests D.C. is a member of the Advisory Board of Molecular Cell.

Références

J Vis Exp. 2017 May 1;(123):
pubmed: 28518126
Elife. 2016 Jul 02;5:
pubmed: 27371829
Genome Biol. 2014;15(12):550
pubmed: 25516281
Mol Cell. 2012 Aug 24;47(4):497-510
pubmed: 22920291
Nat Commun. 2018 Jul 12;9(1):2689
pubmed: 30002377
F1000Res. 2015 Dec 30;4:1521
pubmed: 26925227
J Cell Biol. 2016 Jul 18;214(2):155-66
pubmed: 27432897
Structure. 2010 Aug 11;18(8):955-65
pubmed: 20696396
Cell Death Differ. 2006 Jun;13(6):941-50
pubmed: 16601750
J Cell Biol. 2016 Jul 18;214(2):143-53
pubmed: 27432896
Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):6098-102
pubmed: 8016121
EMBO J. 2019 Aug 15;38(16):e101379
pubmed: 31267591
Proc Natl Acad Sci U S A. 2016 Sep 13;113(37):10263-8
pubmed: 27573816
Genes Dev. 2002 Mar 1;16(5):583-93
pubmed: 11877378
Methods Mol Biol. 2018;1688:257-310
pubmed: 29151214
Nature. 2007 Sep 6;449(7158):105-8
pubmed: 17805299
Mol Cell Proteomics. 2014 Jan;13(1):1-17
pubmed: 24056736
Mol Cell. 2016 Oct 6;64(1):51-64
pubmed: 27546791
J Biol Chem. 2008 Dec 12;283(50):34660-6
pubmed: 18840612
EMBO J. 2002 Jul 15;21(14):3863-72
pubmed: 12110597
Mol Cell. 2015 Mar 19;57(6):1034-1046
pubmed: 25794615
Cell Rep. 2019 Apr 2;27(1):48-58.e7
pubmed: 30943414
Cell. 2006 Dec 29;127(7):1361-73
pubmed: 17190600
J Biol Chem. 2017 Apr 21;292(16):6461-6467
pubmed: 28213517
Mol Cell. 2016 Oct 6;64(1):3-4
pubmed: 27716486
Nature. 2012 Oct 4;490(7418):61-70
pubmed: 23000897
Nat Med. 2017 Jun;23(6):703-713
pubmed: 28481359
Biochemistry. 2009 May 12;48(18):3798-800
pubmed: 19334741
Cell Death Differ. 2018 Jan;25(1):133-143
pubmed: 29125602
J Mol Biol. 2010 May 14;398(4):489-96
pubmed: 20307547
Nucleic Acids Res. 2018 Sep 19;46(16):8153-8167
pubmed: 30107566
Structure. 2015 Feb 3;23(2):312-21
pubmed: 25579814
Nat Commun. 2018 May 29;9(1):2123
pubmed: 29844495
Nat Struct Mol Biol. 2018 Jul;25(7):591-600
pubmed: 29967538
Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2259-64
pubmed: 14982997
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Mol Cell Biol. 2005 Nov;25(22):10079-86
pubmed: 16260621
Nucleic Acids Res. 2019 Jan 8;47(D1):D766-D773
pubmed: 30357393
Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3310-5
pubmed: 16492765
Protein Sci. 2004 Mar;13(3):617-25
pubmed: 14978302
Mol Cell Biol. 1997 Nov;17(11):6255-64
pubmed: 9343386
Curr Opin Cell Biol. 2018 Apr;51:65-72
pubmed: 29195118
Cell Death Differ. 2006 Jun;13(6):951-61
pubmed: 16575405
Mol Cell. 2008 Feb 15;29(3):392-400
pubmed: 18280244
Cell. 2018 Apr 5;173(2):291-304.e6
pubmed: 29625048
Nat Rev Cancer. 2014 May;14(5):359-70
pubmed: 24739573
Trends Cell Biol. 2014 Feb;24(2):108-17
pubmed: 24094932
Nature. 2017 Mar 9;543(7644):211-216
pubmed: 28241136
Mol Cell. 2007 Aug 17;27(4):636-46
pubmed: 17707234
J Cell Biol. 2019 Sep 2;218(9):2865-2875
pubmed: 31366665

Auteurs

Nishita Parnandi (N)

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.

Veronica Rendo (V)

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.

Gaofeng Cui (G)

Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.

Maria Victoria Botuyan (MV)

Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.

Michaela Remisova (M)

Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland.

Huy Nguyen (H)

Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

Pascal Drané (P)

Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

Rameen Beroukhim (R)

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.

Matthias Altmeyer (M)

Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland.

Georges Mer (G)

Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.

Dipanjan Chowdhury (D)

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.

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Sites de fixation › TIRR inhibits the 53BP1-p53 complex to alter...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de transport › TIRR inhibits the 53BP1-p53 complex to alter...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › TIRR inhibits the 53BP1-p53 complex to alter...
questionsmedicales.fr › Phénomènes physiologiques des appareils urinaire et reproducteur › Phénomènes physiologiques de la reproduction › Reproduction › Développement embryonnaire et foetal › Développement embryonnaire › Lignage cellulaire › TIRR inhibits the 53BP1-p53 complex to alter...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ADN › TIRR inhibits the 53BP1-p53 complex to alter...
questionsmedicales.fr › Phénomènes génétiques › Altération de l'ADN › Cassures de l'ADN › Cassures double-brin de l'ADN › TIRR inhibits the 53BP1-p53 complex to alter...
questionsmedicales.fr › Phénomènes génétiques › Réparation de l'ADN › TIRR inhibits the 53BP1-p53 complex to alter...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Histone › TIRR inhibits the 53BP1-p53 complex to alter...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › TIRR inhibits the 53BP1-p53 complex to alter...
questionsmedicales.fr › Métabolisme › Liaison aux protéines › TIRR inhibits the 53BP1-p53 complex to alter...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Protéines de liaison à l'ARN › TIRR inhibits the 53BP1-p53 complex to alter...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Éléments structuraux des protéines › Motifs et domaines d'intéraction protéique › Domaine Tudor › TIRR inhibits the 53BP1-p53 complex to alter...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Phosphoprotéines › Protéine p53 suppresseur de tumeur › TIRR inhibits the 53BP1-p53 complex to alter...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Protéines chromosomiques nonhistones › Protéine-1 liant le suppresseur de tumeur p53 › TIRR inhibits the 53BP1-p53 complex to alter...