XAB2 promotes Ku eviction from single-ended DNA double-strand breaks  independently of the ATM kinase.

Alkylating Agents; MRE11 protein, human; RAD52 protein, human; RNA Splicing Factors; RNA, Small Interfering; Rad52 DNA Repair and Recombination Protein; XAB2 protein, human; EC 2.7.11.1 (ATM protein, human); EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins); EC 2.7.7.- (RAD51 protein, human); EC 2.7.7.- (Rad51 Recombinase); EC 3.1.- (Endodeoxyribonucleases); EC 3.1.- (MRE11 Homologue Protein); EC 3.1.- (RBBP8 protein, human); EC 3.6.4.12 (XRCC5 protein, human); EC 4.2.99.- (Ku Autoantigen); XT3Z54Z28A (Camptothecin); YF1K15M17Y (Temozolomide); Alkylating Agents/adverse effects/pharmacology; Ataxia Telangiectasia Mutated Proteins/metabolism; Camptothecin/adverse effects/pharmacology; 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/metabolism; RNA, Small Interfering/genetics; Rad51 Recombinase/metabolism; Rad52 DNA Repair and Recombination Protein/metabolism; Temozolomide/adverse effects/pharmacology

Abstract :

[en] 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.

Disciplines :

Oncology

Author, co-author :

Sharma, Abhishek Bharadwaj ; DNA Repair and Chemoresistance Group, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg.

Erasimus, Hélène; DNA Repair and Chemoresistance Group, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg. ; Faculty of Science, Technology and Communication, University of Luxembourg, Esch-sur-Alzette, Luxembourg.

Pinto, Lia; DNA Repair and Chemoresistance Group, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg. ; Faculty of Science, Technology and Communication, University of Luxembourg, Esch-sur-Alzette, Luxembourg.

Caron, Marie-Christine; CHU de Québec Research Center, Oncology Division, Québec City, Canada. ; Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research Center, Québec City, Canada.

Gopaul, Diyavarshini; Institut de Génétique Humaine, CNRS et Université de Montpellier, Equipe Labellisée Ligue Contre le Cancer, Montpellier, France.

Peterlini, Thibaut; CHU de Québec Research Center, Oncology Division, Québec City, Canada. ; Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research Center, Québec City, Canada.

Neumann, Katrin; DNA Repair and Chemoresistance Group, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg.

NAZAROV, Petr ; Quantitative Biology Unit, Multiomics Data Science Group, LIH, Luxembourg.

FRITAH, Sabrina ; NorLux Neuro-Oncology Laboratory, Department of Oncology, LIH, Luxembourg.

KLINK, Barbara ; National Center of Genetics, Laboratoire National de Santé, Dudelange, Luxembourg. ; Functional Tumour Genetics Group, Department of Oncology, LIH, Luxembourg.

More authors (7 more)

External co-authors :

yes

Language :

English

Title :

XAB2 promotes Ku eviction from single-ended DNA double-strand breaks independently of the ATM kinase.

Publication date :

27 September 2021

Journal title :

Nucleic Acids Research

ISSN :

0305-1048

eISSN :

1362-4962

Publisher :

Oxford University Press, United Kingdom

Volume :

Issue :

Pages :

9906-9925

Peer reviewed :

Peer Reviewed verified by ORBi

Funding number :

FDN388879/CIHR/Canada

Commentary :

Available on ORBilu :

since 26 February 2024

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