Temporally distinct post-replicative repair mechanisms fill PRIMPOL-dependent ssDNA gaps in human cells.
Antineoplastic Agents
/ pharmacology
BRCA1 Protein
/ genetics
BRCA2 Protein
/ metabolism
Cell Line, Tumor
DNA Breaks, Single-Stranded
DNA Helicases
/ genetics
DNA Primase
/ genetics
DNA Repair
DNA Replication
DNA, Neoplasm
/ biosynthesis
DNA-Binding Proteins
/ genetics
DNA-Directed DNA Polymerase
/ genetics
G2 Phase
Genomic Instability
HEK293 Cells
Humans
MRE11 Homologue Protein
/ genetics
Multifunctional Enzymes
/ genetics
Neoplasms
/ drug therapy
Nucleotidyltransferases
/ genetics
Proliferating Cell Nuclear Antigen
/ genetics
S Phase
Time Factors
Ubiquitin-Conjugating Enzymes
/ genetics
Ubiquitin-Protein Ligases
/ genetics
Ubiquitination
BRCA1
BRCA2
DNA damage tolerance
DNA replication
PRIMPOL
genome stability
post-replicative repair
replication stress
ssDNA gaps
translesion synthesis polymerases
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
07 10 2021
07 10 2021
Historique:
received:
05
02
2021
revised:
20
07
2021
accepted:
10
09
2021
entrez:
8
10
2021
pubmed:
9
10
2021
medline:
31
12
2021
Statut:
ppublish
Résumé
PRIMPOL repriming allows DNA replication to skip DNA lesions, leading to ssDNA gaps. These gaps must be filled to preserve genome stability. Using a DNA fiber approach to directly monitor gap filling, we studied the post-replicative mechanisms that fill the ssDNA gaps generated in cisplatin-treated cells upon increased PRIMPOL expression or when replication fork reversal is defective because of SMARCAL1 inactivation or PARP inhibition. We found that a mechanism dependent on the E3 ubiquitin ligase RAD18, PCNA monoubiquitination, and the REV1 and POLζ translesion synthesis polymerases promotes gap filling in G2. The E2-conjugating enzyme UBC13, the RAD51 recombinase, and REV1-POLζ are instead responsible for gap filling in S, suggesting that temporally distinct pathways of gap filling operate throughout the cell cycle. Furthermore, we found that BRCA1 and BRCA2 promote gap filling by limiting MRE11 activity and that simultaneously targeting fork reversal and gap filling enhances chemosensitivity in BRCA-deficient cells.
Identifiants
pubmed: 34624216
pii: S1097-2765(21)00747-4
doi: 10.1016/j.molcel.2021.09.013
pmc: PMC8555837
mid: NIHMS1741991
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
BRCA1 Protein
0
BRCA1 protein, human
0
BRCA2 Protein
0
BRCA2 protein, human
0
DNA, Neoplasm
0
DNA-Binding Proteins
0
MRE11 protein, human
0
Multifunctional Enzymes
0
PCNA protein, human
0
Proliferating Cell Nuclear Antigen
0
RAD18 protein, human
0
UBE2N protein, human
EC 2.3.2.23
Ubiquitin-Conjugating Enzymes
EC 2.3.2.23
Ubiquitin-Protein Ligases
EC 2.3.2.27
DNA Primase
EC 2.7.7.-
Nucleotidyltransferases
EC 2.7.7.-
PrimPol protein, human
EC 2.7.7.-
REV1 protein, human
EC 2.7.7.-
SMARCAL1 protein, human
EC 2.7.7.-
DNA-Directed DNA Polymerase
EC 2.7.7.7
REV3L protein, human
EC 2.7.7.7
MRE11 Homologue Protein
EC 3.1.-
DNA Helicases
EC 3.6.4.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
4026-4040.e8Subventions
Organisme : NCI NIH HHS
ID : F30 CA254215
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA237263
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA248526
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
Références
Genetics. 2000 Aug;155(4):1633-41
pubmed: 10924462
Adv Protein Chem Struct Biol. 2009;78:99-146
pubmed: 20663485
Mol Cell. 2013 Nov 21;52(4):566-73
pubmed: 24267451
Mol Cell. 2020 Feb 6;77(3):461-474.e9
pubmed: 31676232
Cell. 2019 Jun 27;178(1):152-159.e11
pubmed: 31178121
Clin Cancer Res. 2019 Jul 1;25(13):3759-3771
pubmed: 30760478
Nat Commun. 2017 Oct 16;8(1):859
pubmed: 29038466
Cancer Surv. 1996;28:21-31
pubmed: 8977026
Mol Cell. 2015 Aug 6;59(3):478-90
pubmed: 26253028
Cell. 1994 Nov 18;79(4):573-82
pubmed: 7954824
Cell. 2012 Aug 31;150(5):922-33
pubmed: 22921915
Crit Rev Biochem Mol Biol. 2019 Oct;54(5):418-442
pubmed: 31736364
Nat Struct Mol Biol. 2013 Mar;20(3):347-54
pubmed: 23396353
Nucleic Acids Res. 2019 Feb 20;47(3):1294-1310
pubmed: 29917110
Genes Dev. 2021 Sep 1;35(17-18):1271-1289
pubmed: 34385259
Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13558-63
pubmed: 23901102
Cell. 1999 Mar 5;96(5):645-53
pubmed: 10089880
Nucleic Acids Res. 2009 Sep;37(17):5737-48
pubmed: 19654238
Methods Enzymol. 2017;591:55-82
pubmed: 28645379
Cell. 1989 Sep 8;58(5):833-46
pubmed: 2570636
DNA Repair (Amst). 2019 May;77:65-75
pubmed: 30889508
Crit Rev Biochem Mol Biol. 2017 Jun;52(3):274-303
pubmed: 28279077
Mol Cell. 2013 Feb 7;49(3):536-46
pubmed: 23260657
Eur J Biochem. 1972 Dec 18;31(3):438-45
pubmed: 4675366
Nat Methods. 2006 Dec;3(12):995-1000
pubmed: 17072308
EMBO J. 2004 Oct 1;23(19):3886-96
pubmed: 15359278
Nat Chem Biol. 2008 Feb;4(2):119-25
pubmed: 18176557
Int J Cancer. 1970 Sep 15;6(2):207-16
pubmed: 5479434
Cell. 2010 Apr 16;141(2):255-67
pubmed: 20403322
DNA Repair (Amst). 2009 Dec 3;8(12):1444-51
pubmed: 19783229
Cancer Res. 2021 Mar 1;81(5):1388-1397
pubmed: 33184108
Nat Struct Mol Biol. 2012 Mar 04;19(4):417-23
pubmed: 22388737
Am J Med Genet A. 2015 Oct;167A(10):2260-4
pubmed: 25943327
Eur J Pediatr. 2000 Jan-Feb;159(1-2):1-7
pubmed: 10653321
EMBO J. 2019 Feb 1;38(3):
pubmed: 30478192
Nucleic Acids Res. 2011 Sep 1;39(16):7049-57
pubmed: 21646340
DNA Repair (Amst). 2014 Feb;14:27-38
pubmed: 24380689
Mol Cell. 2008 May 23;30(4):519-29
pubmed: 18498753
DNA Repair (Amst). 2016 Aug;44:68-75
pubmed: 27236213
Mol Cell. 2006 Jan 6;21(1):15-27
pubmed: 16387650
Mol Cell. 2002 Oct;10(4):917-24
pubmed: 12419234
Genes Dev. 2005 Feb 1;19(3):339-50
pubmed: 15687257
Cell Cycle. 2016 Aug 2;15(15):1997-2008
pubmed: 27230014
Nat Struct Mol Biol. 2010 Nov;17(11):1305-11
pubmed: 20935632
Nature. 2006 Feb 2;439(7076):557-62
pubmed: 16452972
EMBO J. 2021 Jul 15;40(14):e106355
pubmed: 34128550
Nucleic Acids Res. 2014 Oct 29;42(19):12102-11
pubmed: 25262353
DNA Repair (Amst). 2018 Nov;71:172-176
pubmed: 30177437
Nature. 2002 Sep 12;419(6903):135-41
pubmed: 12226657
ACS Chem Biol. 2011 Jun 17;6(6):628-35
pubmed: 21428443
Nat Rev Clin Oncol. 2018 Sep;15(9):564-576
pubmed: 29955114
Mol Cell. 2020 Jun 18;78(6):1237-1251.e7
pubmed: 32442397
Genes Dev. 2017 Feb 1;31(3):318-332
pubmed: 28242626
Mol Cell. 2021 Feb 18;81(4):649-658
pubmed: 33515486
PLoS Genet. 2015 Dec 29;11(12):e1005757
pubmed: 26713761
J Cell Sci. 2020 Oct 30;133(20):
pubmed: 32989039
Nat Commun. 2020 May 1;11(1):2147
pubmed: 32358495
EMBO J. 2003 Jun 16;22(12):3188-97
pubmed: 12805232
Mol Cell. 2017 Sep 7;67(5):867-881.e7
pubmed: 28757209
EMBO J. 2009 Dec 2;28(23):3657-66
pubmed: 19851286
Nucleic Acids Res. 2012 Jan;40(2):682-91
pubmed: 21926160
Genes Dev. 1994 Apr 1;8(7):811-20
pubmed: 7926769
Nucleic Acids Res. 2012 Jan;40(1):170-80
pubmed: 21908406
Nat Commun. 2017 Oct 16;8(1):860
pubmed: 29038425
Mol Cell. 2015 Mar 5;57(5):812-823
pubmed: 25661486
Mol Cell Biol. 2005 Jul;25(14):6103-11
pubmed: 15988022
J Ovarian Res. 2009 Jan 14;2:2
pubmed: 19144189
Nat Rev Mol Cell Biol. 2015 Apr;16(4):207-20
pubmed: 25714681
EMBO J. 2009 Feb 18;28(4):383-93
pubmed: 19153606
Mol Cell. 2004 May 21;14(4):491-500
pubmed: 15149598
Mol Cell. 2019 Mar 7;73(5):900-914.e9
pubmed: 30733119
Nucleic Acids Res. 2016 Dec 15;44(22):10727-10743
pubmed: 27694624
Annu Rev Biochem. 2005;74:317-53
pubmed: 15952890
Mol Cell. 2007 Mar 9;25(5):663-75
pubmed: 17349954
Nature. 2010 Jun 17;465(7300):951-5
pubmed: 20453836
Biochim Biophys Acta. 1976 Apr 2;425(4):419-27
pubmed: 130925
Nucleic Acids Res. 2016 Jul 8;44(12):5717-31
pubmed: 27095204
Sci Adv. 2020 Jun 10;6(24):eaaz7808
pubmed: 32577513
Mol Cell. 2018 Dec 20;72(6):925-941.e4
pubmed: 30576655
Mol Cell. 2021 Aug 5;81(15):3227
pubmed: 34358459
Mol Cell. 2016 Jan 7;61(1):161-9
pubmed: 26626482
Proc Natl Acad Sci U S A. 2015 Dec 1;112(48):E6624-33
pubmed: 26627254
Crit Rev Biochem Mol Biol. 2021 Feb;56(1):17-30
pubmed: 33179522
Sci Adv. 2020 Nov 13;6(46):
pubmed: 33188024
PLoS Genet. 2010 Nov 11;6(11):e1001205
pubmed: 21085632
J Cell Biol. 1998 Mar 23;140(6):1285-95
pubmed: 9508763
J Cell Biol. 2015 Mar 2;208(5):563-79
pubmed: 25733714
Proc Natl Acad Sci U S A. 2001 May 22;98(11):6086-91
pubmed: 11353843
Mol Cell Biol. 2010 Mar;30(5):1217-30
pubmed: 20028736
J Biol Chem. 2008 Mar 21;283(12):7713-20
pubmed: 18171670
EMBO Rep. 2013 Dec;14(12):1104-12
pubmed: 24126761
Mol Cell. 2021 Feb 18;81(4):784-800.e8
pubmed: 33412112
Nat Methods. 2012 Jul;9(7):671-5
pubmed: 22930834
Nat Commun. 2020 Nov 17;11(1):5863
pubmed: 33203852
EMBO J. 2014 Feb 18;33(4):327-40
pubmed: 24473148
Proc Natl Acad Sci U S A. 2012 May 15;109(20):7799-804
pubmed: 22547805
Mol Cell. 2013 Nov 21;52(4):541-53
pubmed: 24207056
Nat Struct Mol Biol. 2013 Dec;20(12):1383-9
pubmed: 24240614
DNA Repair (Amst). 2012 Jun 1;11(6):550-8
pubmed: 22521143
Trends Genet. 2018 Jul;34(7):518-531
pubmed: 29735283
Nat Struct Mol Biol. 2006 Oct;13(10):915-20
pubmed: 16980971
Methods Mol Biol. 2014;1094:177-208
pubmed: 24162989
Nat Commun. 2019 Mar 29;10(1):1412
pubmed: 30926821
Genes Dev. 2006 Jan 1;20(1):34-46
pubmed: 16391231
Mol Cell Biol. 2004 Nov;24(21):9478-86
pubmed: 15485915
Nucleus. 2010 May-Jun;1(3):245-8
pubmed: 21327070
Mol Cell. 2017 Oct 19;68(2):414-430.e8
pubmed: 29053959