ATR promotes clearance of damaged DNA and damaged cells by rupturing micronuclei.

Humans Lamin Type A / genetics Phosphorylation DNA Damage Nucleotidyltransferases / genetics DNA / metabolism Ataxia Telangiectasia Mutated Proteins / genetics
ATR CDK1 DNA damage STING TREX1 autophagosome autophagy cGAS cell-autonomous cell-non-autonomous clearance damaged DNA micronuclear DNA micronuclei micronucleus natural killer cells nuclear envelope rupture

Journal

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

Informations de publication

Date de publication:
19 10 2023
Historique:
received: 25 04 2022
revised: 28 06 2023
accepted: 06 09 2023
pmc-release: 19 10 2024
medline: 27 10 2023
pubmed: 4 10 2023
entrez: 3 10 2023
Statut: ppublish

Résumé

The human ataxia telangiectasia mutated and Rad3-related (ATR) kinase functions in the nucleus to protect genomic integrity. Micronuclei (MN) arise from genomic and chromosomal instability and cause aneuploidy and chromothripsis, but how MN are removed is poorly understood. Here, we show that ATR is active in MN and promotes their rupture in S phase by phosphorylating Lamin A/C at Ser395, which primes Ser392 for CDK1 phosphorylation and destabilizes the MN envelope. In cells harboring MN, ATR or CDK1 inhibition reduces MN rupture. Consequently, ATR inhibitor (ATRi) diminishes activation of the cytoplasmic DNA sensor cGAS and compromises cGAS-dependent autophagosome accumulation in MN and clearance of micronuclear DNA. Furthermore, ATRi reduces cGAS-mediated senescence and killing of MN-bearing cancer cells by natural killer cells. Thus, in addition to the canonical ATR signaling pathway, an ATR-CDK1-Lamin A/C axis promotes MN rupture to clear damaged DNA and cells, protecting the genome in cell populations through unexpected cell-autonomous and cell-non-autonomous mechanisms.

Identifiants

DOI: 10.1016/j.molcel.2023.09.003 PMID: 37788673 PMC: PMC10599252
pubmed: 37788673
pii: S1097-2765(23)00698-6
doi: 10.1016/j.molcel.2023.09.003
pmc: PMC10599252
mid: NIHMS1935060
pii:
doi:

Substances chimiques

Lamin Type A 0
Nucleotidyltransferases EC 2.7.7.-
DNA 9007-49-2
Ataxia Telangiectasia Mutated Proteins EC 2.7.11.1
ATR protein, human EC 2.7.11.1

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

3642-3658.e4

Subventions

Organisme : NIGMS NIH HHS
ID : R35 GM150648
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA218856
Pays : United States
Organisme : NCI NIH HHS
ID : K22 CA244865
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA197779
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA275096
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2023 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests L.Z. is a member of the advisory board of Molecular Cell.

Références

Cell. 1990 May 18;61(4):591-602
pubmed: 2188731
Nature. 2009 Jul 9;460(7252):278-82
pubmed: 19506557
Nature. 2019 Mar;567(7747):262-266
pubmed: 30842662
Am J Pathol. 2002 Aug;161(2):391-7
pubmed: 12163363
J Cell Biol. 1991 Oct;115(1):1-17
pubmed: 1717476
Genes Dev. 2007 Apr 15;21(8):898-903
pubmed: 17437996
J Cell Biol. 2007 Jul 16;178(2):257-68
pubmed: 17635936
Nature. 2015 Jun 11;522(7555):179-84
pubmed: 26017310
Sci Rep. 2015 Oct 20;5:15377
pubmed: 26483214
Annu Rev Pathol. 2010;5:99-118
pubmed: 20078217
Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19855-60
pubmed: 18077418
Nat Cell Biol. 2009 Jan;11(1):27-35
pubmed: 19060894
Immunity. 2018 Oct 16;49(4):754-763.e4
pubmed: 30332631
Proc Natl Acad Sci U S A. 2017 Jun 6;114(23):E4612-E4620
pubmed: 28533362
Science. 2007 May 25;316(5828):1160-6
pubmed: 17525332
Cell. 2013 Jul 3;154(1):47-60
pubmed: 23827674
Science. 2018 Aug 24;361(6404):806-810
pubmed: 30139873
Nat Cell Biol. 2016 Nov;18(11):1185-1195
pubmed: 27723720
Sci Rep. 2021 Mar 31;11(1):7243
pubmed: 33790360
Mol Cell. 2019 Oct 3;76(1):11-26.e7
pubmed: 31400850
Nat Rev Immunol. 2021 Sep;21(9):548-569
pubmed: 33833439
J Exp Med. 2018 May 7;215(5):1287-1299
pubmed: 29622565
Genes Dev. 2003 Mar 1;17(5):615-28
pubmed: 12629044
Cell. 1990 May 18;61(4):561-77
pubmed: 2188730
Nucleus. 2012 Jan-Feb;3(1):88-100
pubmed: 22567193
J Cell Biol. 2005 May 9;169(3):391-7
pubmed: 15883193
Science. 2003 Jun 6;300(5625):1542-8
pubmed: 12791985
J Cell Biol. 2011 Jan 10;192(1):17-27
pubmed: 21220506
Mol Cell. 2009 Mar 13;33(5):547-58
pubmed: 19285939
Genes Dev. 2000 Jun 15;14(12):1448-59
pubmed: 10859164
Cell Rep. 2020 Sep 1;32(9):108080
pubmed: 32877684
J Virol. 2017 Apr 13;91(9):
pubmed: 28179534
Nat Rev Mol Cell Biol. 2017 Oct;18(10):622-636
pubmed: 28811666
Nature. 2018 Jan 25;553(7689):467-472
pubmed: 29342134
Science. 2000 May 26;288(5470):1425-9
pubmed: 10827953
Cell Rep. 2013 Nov 27;5(4):1095-107
pubmed: 24268773
Nature. 2017 Aug 24;548(7668):461-465
pubmed: 28738408
Cold Spring Harb Perspect Med. 2017 Jan 3;7(1):
pubmed: 28049655
J Cell Biol. 2019 Apr 1;218(4):1235-1249
pubmed: 30755469
Nature. 2017 Aug 24;548(7668):466-470
pubmed: 28759889
Nat Commun. 2020 Sep 24;11(1):4828
pubmed: 32973141
Cancer Discov. 2020 Jan;10(1):26-39
pubmed: 31852718
Cell Cycle. 2012 Jan 1;11(1):170-6
pubmed: 22185757
Genes Dev. 2005 May 1;19(9):1040-52
pubmed: 15833913
Cell. 2014 Jul 31;158(3):633-46
pubmed: 25083873
Nature. 2023 Jul;619(7968):176-183
pubmed: 37286593
Cell. 2008 Jun 13;133(6):1019-31
pubmed: 18555778
Autophagy. 2021 Dec;17(12):3976-3991
pubmed: 33752561
Proc Natl Acad Sci U S A. 2010 Sep 14;107(37):16090-5
pubmed: 20805465
Science. 2018 Jan 5;359(6371):108-114
pubmed: 29170278
Mol Cell Biol. 2006 Apr;26(8):3319-26
pubmed: 16581803
Nature. 2023 Jul;619(7968):184-192
pubmed: 37286600
Dev Cell. 2017 Jun 19;41(6):638-651.e5
pubmed: 28633018
Nat Cell Biol. 2016 Nov;18(11):1196-1207
pubmed: 27723717
Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9092-7
pubmed: 11481475
J Cell Biol. 2006 Apr 24;173(2):195-206
pubmed: 16618811
Nat Cell Biol. 2017 Jan;19(1):68-75
pubmed: 27918550
Nature. 2022 Jun;606(7916):930-936
pubmed: 35477155
Cell. 1990 May 18;61(4):579-89
pubmed: 2344612
Cell Cycle. 2006 Oct;5(19):2203-9
pubmed: 16969104
EMBO J. 2020 Jul 15;39(14):e104036
pubmed: 32484965
Nature. 2006 Nov 30;444(7119):633-7
pubmed: 17136093
Mol Cell. 2021 Feb 18;81(4):724-738.e9
pubmed: 33476576
Cold Spring Harb Perspect Biol. 2013 Sep 01;5(9):
pubmed: 24003211
Mol Cell. 2015 Sep 17;59(6):1011-24
pubmed: 26365377
J Cell Sci. 2014 Jun 15;127(Pt 12):2683-96
pubmed: 24741066
Nature. 2018 Sep;561(7724):551-555
pubmed: 30232450
Nature. 2012 Jan 18;482(7383):53-8
pubmed: 22258507

Auteurs

Yoon Ki Joo (YK)

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA; Yale Cancer Biology Institute, Yale University, New Haven, CT 06516, USA.

Elizabeth M Black (EM)

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA; Yale Cancer Biology Institute, Yale University, New Haven, CT 06516, USA.

Isabelle Trier (I)

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA; Yale Cancer Biology Institute, Yale University, New Haven, CT 06516, USA.

Wisse Haakma (W)

Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Boston, MA 02129, USA.

Lee Zou (L)

Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Boston, MA 02129, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27708, USA. Electronic address: lee.zou@duke.edu.

Lilian Kabeche (L)

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA; Yale Cancer Biology Institute, Yale University, New Haven, CT 06516, USA. Electronic address: lilian.kabeche@yale.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 › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › ATR promotes clearance of damaged DNA and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines nucléaires › Protéines associées à la matrice nucléaire › Lamines › Lamine A › ATR promotes clearance of damaged DNA and...
questionsmedicales.fr › Métabolisme › Phosphorylation › ATR promotes clearance of damaged DNA and...
questionsmedicales.fr › Phénomènes génétiques › Altération de l'ADN › ATR promotes clearance of damaged DNA and...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Phosphotransferases › Nucleotidyltransferases › ATR promotes clearance of damaged DNA and...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ADN › ATR promotes clearance of damaged DNA and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines nucléaires › Protéines liant le poly-adp-ribose › Protéines mutées dans l'ataxie-télangiectasie › ATR promotes clearance of damaged DNA and...