SLFN5-mediated chromatin dynamics sculpt higher-order DNA repair topology.
53BP1
DNA double-strand break repair
PARP inhibitor sensitivity
SLFN5
chromatin mobility
chromatin topology
class switch recombination
non-homologous end joining
super-resolution microscopy
telomere fusions
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
06 04 2023
06 04 2023
Historique:
received:
17
05
2022
revised:
23
12
2022
accepted:
01
02
2023
pmc-release:
06
04
2024
medline:
11
4
2023
pubmed:
1
3
2023
entrez:
28
2
2023
Statut:
ppublish
Résumé
Repair of DNA double-strand breaks (DSBs) elicits three-dimensional (3D) chromatin topological changes. A recent finding reveals that 53BP1 assembles into a 3D chromatin topology pattern around DSBs. How this formation of a higher-order structure is configured and regulated remains enigmatic. Here, we report that SLFN5 is a critical factor for 53BP1 topological arrangement at DSBs. Using super-resolution imaging, we find that SLFN5 binds to 53BP1 chromatin domains to assemble a higher-order microdomain architecture by driving damaged chromatin dynamics at both DSBs and deprotected telomeres. Mechanistically, we propose that 53BP1 topology is shaped by two processes: (1) chromatin mobility driven by the SLFN5-LINC-microtubule axis and (2) the assembly of 53BP1 oligomers mediated by SLFN5. In mammals, SLFN5 deficiency disrupts the DSB repair topology and impairs non-homologous end joining, telomere fusions, class switch recombination, and sensitivity to poly (ADP-ribose) polymerase inhibitor. We establish a molecular mechanism that shapes higher-order chromatin topologies to safeguard genomic stability.
Identifiants
pubmed: 36854302
pii: S1097-2765(23)00083-7
doi: 10.1016/j.molcel.2023.02.004
pmc: PMC10467573
mid: NIHMS1915305
pii:
doi:
Substances chimiques
Chromatin
0
Telomere-Binding Proteins
0
Tumor Suppressor p53-Binding Protein 1
0
Cell Cycle Proteins
0
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
1043-1060.e10Subventions
Organisme : NCI NIH HHS
ID : P30 CA015083
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM065841
Pays : United States
Informations de copyright
Copyright © 2023 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
Références
Cell Res. 2011 Jul;21(7):1028-38
pubmed: 21423270
Br J Cancer. 2020 Aug;123(4):633-643
pubmed: 32488136
Nat Struct Mol Biol. 2017 Feb;24(2):99-107
pubmed: 28067915
Biochem Biophys Res Commun. 2008 May 23;370(1):62-6
pubmed: 18355440
Methods. 2017 Feb 15;115:80-90
pubmed: 27713081
Nature. 2015 May 28;521(7553):541-544
pubmed: 25799992
Mol Cell. 2017 Oct 5;68(1):171-184.e6
pubmed: 28985503
Cell. 2015 Nov 5;163(4):880-93
pubmed: 26544937
Genes Dev. 2021 Oct 1;35(19-20):1356-1367
pubmed: 34503990
Nat Immunol. 2004 May;5(5):481-7
pubmed: 15077110
Nat Cell Biol. 2019 Oct;21(10):1273-1285
pubmed: 31548606
Biomark Res. 2015 May 01;3:9
pubmed: 26015868
Mol Cell. 2011 May 6;42(3):319-29
pubmed: 21549309
Mol Cell Biol. 2014 Apr;34(7):1349-62
pubmed: 24469404
Nat Struct Mol Biol. 2013 Mar;20(3):317-25
pubmed: 23377543
Cell. 2010 Jun 11;141(6):970-81
pubmed: 20550933
Trends Biochem Sci. 2020 Mar;45(3):177-179
pubmed: 31882194
Nat Rev Mol Cell Biol. 2020 Dec;21(12):765-781
pubmed: 33077885
Nature. 2018 Jul;559(7712):54-60
pubmed: 29925946
Redox Biol. 2014 Jan 09;2:457-65
pubmed: 24624335
Mol Cell. 2013 Mar 7;49(5):872-83
pubmed: 23333306
Clin Cancer Res. 2016 Aug 1;22(15):3764-73
pubmed: 26957554
Clin Cancer Res. 2017 Jan 15;23(2):523-535
pubmed: 27440269
Trends Immunol. 2002 Jan;23(1):31-9
pubmed: 11801452
J Cell Biol. 2006 Mar 13;172(6):823-34
pubmed: 16520385
Nat Cell Biol. 2020 Dec;22(12):1460-1470
pubmed: 33257806
Nat Commun. 2018 Mar 21;9(1):1165
pubmed: 29563550
Nature. 2018 Aug;560(7716):112-116
pubmed: 30022158
Nature. 2018 Aug;560(7716):122-127
pubmed: 30046110
Nat Microbiol. 2021 Feb;6(2):234-245
pubmed: 33432153
Cell. 2018 May 3;173(4):972-988.e23
pubmed: 29656893
Trends Genet. 2019 Sep;35(9):685-705
pubmed: 31371030
Cell. 2000 Sep 1;102(5):553-63
pubmed: 11007474
Gene. 2009 Nov 1;447(1):1-11
pubmed: 19619625
Genes Dev. 2017 Nov 15;31(22):2204-2221
pubmed: 29284710
Science. 2021 May 14;372(6543):
pubmed: 33986151
Nature. 2018 Jul;559(7712):61-66
pubmed: 29925947
Cell Rep. 2018 Apr 03;23(1):239-254.e6
pubmed: 29617664
Int Immunol. 2004 Oct;16(10):1535-48
pubmed: 15351786
Nat Cell Biol. 2022 Jan;24(1):51-61
pubmed: 35027730
Cell Biol Int. 2018 Jan;42(1):2-8
pubmed: 28460425
Cell Rep. 2017 Jan 31;18(5):1200-1214
pubmed: 28147275
Sci Adv. 2021 Jun 2;7(23):
pubmed: 34078602
IEEE Trans Image Process. 1998;7(1):27-41
pubmed: 18267377
Proc Natl Acad Sci U S A. 2019 Apr 9;116(15):7323-7332
pubmed: 30918123
Oncogene. 2017 Oct 26;36(43):6006-6019
pubmed: 28671669
Nat Struct Mol Biol. 2019 Dec;26(12):1087-1088
pubmed: 31792447
Mol Cell. 2020 Sep 3;79(5):824-835.e5
pubmed: 32649882
Pharmacol Ther. 2019 Sep;201:94-102
pubmed: 31128155
J Cell Biol. 2014 Jan 20;204(2):231-45
pubmed: 24446482
Nat Cell Biol. 2018 Aug;20(8):954-965
pubmed: 30022119
Nat Cell Biol. 2021 Aug;23(8):894-904
pubmed: 34354233
Nat Commun. 2017 Feb 08;8:14244
pubmed: 28176781
Mol Cell. 2018 Feb 1;69(3):371-384.e6
pubmed: 29395061
Mol Cell. 2013 Mar 7;49(5):858-71
pubmed: 23333305
Nature. 2008 Nov 27;456(7221):524-8
pubmed: 18931659
Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2146-51
pubmed: 23345425
Nature. 2012 Nov 1;491(7422):125-8
pubmed: 23000900
Nat Rev Mol Cell Biol. 2014 Jan;15(1):7-18
pubmed: 24326623
Nature. 2018 Aug;560(7716):117-121
pubmed: 30022168
Science. 2013 Feb 8;339(6120):700-4
pubmed: 23306437
EMBO Rep. 2019 May;20(5):
pubmed: 30948458
Elife. 2021 May 04;10:
pubmed: 33942717
J Cell Sci. 2012 Aug 1;125(Pt 15):3529-34
pubmed: 22553214
EMBO Rep. 2016 Jan;17(1):94-109
pubmed: 26658330
Am J Cancer Res. 2020 Sep 01;10(9):2832-2850
pubmed: 33042620
Cell Rep. 2019 Aug 6;28(6):1389-1399.e6
pubmed: 31390554
Genes Dev. 2020 Jan 1;34(1-2):7-23
pubmed: 31896689
Nature. 2019 Oct;574(7779):571-574
pubmed: 31645724
Cell. 2010 Apr 16;141(2):243-54
pubmed: 20362325
Trends Biochem Sci. 2019 Jul;44(7):565-574
pubmed: 31072688
Nat Rev Mol Cell Biol. 2019 Nov;20(11):698-714
pubmed: 31263220