XAB2 promotes Ku eviction from single-ended DNA double-strand breaks independently of the ATM kinase.
Alkylating Agents
/ adverse effects
Ataxia Telangiectasia Mutated Proteins
/ metabolism
Camptothecin
/ adverse effects
Cell Line, Tumor
DNA Breaks, Double-Stranded
DNA End-Joining Repair
/ genetics
Endodeoxyribonucleases
/ metabolism
Glioblastoma
/ drug therapy
Homologous Recombination
/ genetics
Humans
Ku Autoantigen
/ metabolism
MRE11 Homologue Protein
/ metabolism
RNA Interference
RNA Splicing Factors
/ genetics
RNA, Small Interfering
/ genetics
Rad51 Recombinase
/ metabolism
Rad52 DNA Repair and Recombination Protein
/ metabolism
Temozolomide
/ adverse effects
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
27 09 2021
27 09 2021
Historique:
accepted:
01
09
2021
revised:
16
08
2021
received:
21
05
2021
pubmed:
10
9
2021
medline:
21
12
2021
entrez:
9
9
2021
Statut:
ppublish
Résumé
Replication-associated single-ended DNA double-strand breaks (seDSBs) are repaired predominantly through RAD51-mediated homologous recombination (HR). Removal of the non-homologous end-joining (NHEJ) factor Ku from resected seDSB ends is crucial for HR. The coordinated actions of MRE11-CtIP nuclease activities orchestrated by ATM define one pathway for Ku eviction. Here, we identify the pre-mRNA splicing protein XAB2 as a factor required for resistance to seDSBs induced by the chemotherapeutic alkylator temozolomide. Moreover, we show that XAB2 prevents Ku retention and abortive HR at seDSBs induced by temozolomide and camptothecin, via a pathway that operates in parallel to the ATM-CtIP-MRE11 axis. Although XAB2 depletion preserved RAD51 focus formation, the resulting RAD51-ssDNA associations were unproductive, leading to increased NHEJ engagement in S/G2 and genetic instability. Overexpression of RAD51 or RAD52 rescued the XAB2 defects and XAB2 loss was synthetically lethal with RAD52 inhibition, providing potential perspectives in cancer therapy.
Identifiants
pubmed: 34500463
pii: 6368059
doi: 10.1093/nar/gkab785
pmc: PMC8464071
doi:
Substances chimiques
Alkylating Agents
0
MRE11 protein, human
0
RAD52 protein, human
0
RNA Splicing Factors
0
RNA, Small Interfering
0
Rad52 DNA Repair and Recombination Protein
0
XAB2 protein, human
0
ATM protein, human
EC 2.7.11.1
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
RAD51 protein, human
EC 2.7.7.-
Rad51 Recombinase
EC 2.7.7.-
Endodeoxyribonucleases
EC 3.1.-
MRE11 Homologue Protein
EC 3.1.-
RBBP8 protein, human
EC 3.1.-
XRCC5 protein, human
EC 3.6.4.12
Ku Autoantigen
EC 4.2.99.-
Camptothecin
XT3Z54Z28A
Temozolomide
YF1K15M17Y
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
9906-9925Subventions
Organisme : CIHR
ID : FDN388879
Pays : Canada
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.
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