RAD51 is a druggable target that sustains replication fork progression upon DNA replication stress.
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2022
2022
Historique:
received:
22
03
2022
accepted:
19
07
2022
entrez:
15
8
2022
pubmed:
16
8
2022
medline:
18
8
2022
Statut:
epublish
Résumé
Solving the problems that replication forks encounter when synthesizing DNA is essential to prevent genomic instability. Besides their role in DNA repair in the G2 phase, several homologous recombination proteins, specifically RAD51, have prominent roles in the S phase. Using different cellular models, RAD51 has been shown not only to be present at ongoing and arrested replication forks but also to be involved in nascent DNA protection and replication fork restart. Through pharmacological inhibition, here we study the specific role of RAD51 in the S phase. RAD51 inhibition in non-transformed cell lines did not have a significant effect on replication fork progression under non-perturbed conditions, but when the same cells were subjected to replication stress, RAD51 became necessary to maintain replication fork progression. Notably, the inhibition or depletion of RAD51 did not compromise fork integrity when subjected to hydroxyurea treatment. RAD51 inhibition also did not decrease the ability to restart, but rather compromised fork progression during reinitiation. In agreement with the presence of basal replication stress in human colorectal cancer cells, RAD51 inhibition reduced replication fork speed in these cells and increased γH2Ax foci under control conditions. These alterations could have resulted from the reduced association of DNA polymerase α to chromatin, as observed when inhibiting RAD51. It may be possible to exploit the differential dependence of non-transformed cells versus colorectal cancer cells on RAD51 activity under basal conditions to design new therapies that specifically target cancer cells.
Identifiants
pubmed: 35969531
doi: 10.1371/journal.pone.0266645
pii: PONE-D-22-08515
pmc: PMC9377619
doi:
Substances chimiques
DNA-Binding Proteins
0
DNA
9007-49-2
RAD51 protein, human
EC 2.7.7.-
Rad51 Recombinase
EC 2.7.7.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0266645Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
Front Oncol. 2014 Oct 30;4:289
pubmed: 25401086
EMBO J. 2013 May 2;32(9):1307-21
pubmed: 23563117
Nat Struct Mol Biol. 2011 Nov 27;18(12):1331-1335
pubmed: 22120667
Nat Struct Mol Biol. 2010 Nov;17(11):1305-11
pubmed: 20935632
PLoS One. 2014 Jun 27;9(6):e100993
pubmed: 24971740
Cell Rep. 2013 Apr 25;3(4):1252-65
pubmed: 23562156
Nat Commun. 2017 Oct 16;8(1):859
pubmed: 29038466
DNA Repair (Amst). 2009 Sep 2;8(9):1038-46
pubmed: 19482564
Curr Opin Struct Biol. 2016 Apr;37:145-51
pubmed: 26866665
Cancer Res. 2019 Apr 15;79(8):1730-1739
pubmed: 30967400
Stem Cell Reports. 2017 Jan 10;8(1):125-139
pubmed: 28076755
Nature. 2016 Jul 20;535(7612):382-7
pubmed: 27443740
Annu Rev Biochem. 2008;77:229-57
pubmed: 18275380
Int J Cancer. 2013 May 1;132(9):2118-26
pubmed: 23065657
Nat Commun. 2019 Sep 27;10(1):4410
pubmed: 31562309
Cell Rep. 2018 Jul 17;24(3):538-545
pubmed: 30021152
Int J Cancer. 2000 Dec 15;88(6):907-13
pubmed: 11093813
Mol Oncol. 2017 May;11(5):470-490
pubmed: 28173629
Cell Mol Life Sci. 2020 Feb;77(4):735-749
pubmed: 31297568
Mutat Res. 2018 May;809:58-69
pubmed: 28501329
Nat Commun. 2020 Jul 15;11(1):3531
pubmed: 32669601
Nat Struct Mol Biol. 2008 Oct;15(10):1049-58
pubmed: 18794841
Nat Rev Cancer. 2015 May;15(5):276-89
pubmed: 25907220
Eur J Biochem. 1997 Jan 15;243(1-2):527-36
pubmed: 9030781
Semin Cancer Biol. 2016 Jun;37-38:16-25
pubmed: 26805514
Biomolecules. 2012 Dec 1;2(4):483-504
pubmed: 23767011
Annu Rev Genet. 2020 Nov 23;54:25-46
pubmed: 32663049
Nat Rev Mol Cell Biol. 2010 Mar;11(3):208-19
pubmed: 20177396
Cancer Cell. 2007 Mar;11(3):291-302
pubmed: 17349585
Cell Rep. 2018 Nov 20;25(8):2061-2069.e4
pubmed: 30463005
FEBS Lett. 2017 Apr;591(8):1083-1100
pubmed: 28079255
Mol Cell. 2017 Sep 7;67(5):867-881.e7
pubmed: 28757209
Cell Cycle. 2012 Oct 1;11(19):3627-37
pubmed: 22935704
Cell Rep. 2017 Oct 10;21(2):333-340
pubmed: 29020621
Nat Commun. 2019 Feb 22;10(1):910
pubmed: 30796221
Cell Rep. 2019 Oct 15;29(3):551-559.e4
pubmed: 31618626
Science. 2014 Jan 3;343(6166):88-91
pubmed: 24310611
Cancer Cell. 2012 Jul 10;22(1):106-16
pubmed: 22789542
Nucleic Acids Res. 2016 Jun 2;44(10):4745-62
pubmed: 26939887
Nat Struct Mol Biol. 2011 Dec 04;19(1):17-24
pubmed: 22139015
Nat Rev Mol Cell Biol. 2015 Apr;16(4):207-20
pubmed: 25714681
Cell. 2011 Apr 29;145(3):435-46
pubmed: 21529715
FASEB J. 2020 May;34(5):6907-6919
pubmed: 32267586
Cancer Res. 2002 Jan 1;62(1):219-25
pubmed: 11782381
Chromosoma. 2017 Feb;126(1):1-15
pubmed: 26797216
Cell. 2011 May 13;145(4):529-42
pubmed: 21565612
Nucleic Acids Res. 2015 Nov 16;43(20):9835-55
pubmed: 26354865
Nucleic Acids Res. 2019 Jul 26;47(13):6796-6810
pubmed: 31114910
Annu Rev Biochem. 2018 Jun 20;87:217-238
pubmed: 29298091
J Med Chem. 2012 Apr 12;55(7):3011-20
pubmed: 22380680
Sci Adv. 2020 Nov 13;6(46):
pubmed: 33188024
Oncotarget. 2016 Sep 13;7(37):58759-58767
pubmed: 27577084
J Cell Biol. 2015 Mar 2;208(5):563-79
pubmed: 25733714
Nat Struct Mol Biol. 2018 Jun;25(6):446-453
pubmed: 29807999
Genet Mol Biol. 2019 Dec 13;43(1 suppl 1):e20190138
pubmed: 31930281
Annu Rev Pathol. 2015;10:425-48
pubmed: 25621662
Nature. 2013 Feb 28;494(7438):492-496
pubmed: 23446422
Mol Cancer Ther. 2018 Jul;17(7):1392-1404
pubmed: 29654063
Mol Cell. 2019 Jun 6;74(5):866-876
pubmed: 31173722
Nucleic Acids Res. 2019 Nov 4;47(19):10151-10165
pubmed: 31665741
Nat Cell Biol. 2014 Jan;16(1):2-9
pubmed: 24366029
Mol Cell. 2010 Feb 26;37(4):492-502
pubmed: 20188668
Mol Cell. 2017 Dec 7;68(5):830-833
pubmed: 29220651