TY - JOUR
T1 - XAB2 promotes Ku eviction from single-ended DNA double-strand breaks independently of the ATM kinase
AU - Sharma, Abhishek Bharadwaj
AU - Pinto, Lia
AU - Erasimus, Hélène
AU - Caron, Marie Christine
AU - Gopaul, DIyavarshini
AU - Peterlini, Thibaut
AU - Neumann, Katrin
AU - Nazarov, Petr V.
AU - Fritah, Sabrina
AU - Klink, Barbara
AU - Herold-Mende, Christel C.
AU - Niclou, Simone P.
AU - Pasero, Philippe
AU - Calsou, Patrick
AU - Masson, Jean Yves
AU - Britton, Sébastien
AU - Van Dyck, Eric
N1 - Televie/Fonds National de la Recherche (F.R.S.- FNRS)/Fonds National de la Recherche du Luxembourg (FNR) [7.4503.11 to H.E. and E.V.D., 7.4633.16 to A.B.S. and E.V.D.]; Doctoral School for Systems and Molecular Biomedicine, University of Luxembourg (to H.E.); FNR (PRIDE grant to L.P.); Ligue Nationale Contre le Cancer (to P.P.); Canadian Institutes of Health Research Foundation grant [FDN388879 to J.-Y.M.]; J.-Y.M. is a FRQS chair in genome stability; D.G. thanks the Fondation Recherche Médicale. Funding for open access charge: Internal budget.
Publisher Copyright:
© 2021 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research.
PY - 2021/9/27
Y1 - 2021/9/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85117363012&partnerID=8YFLogxK
UR - https://www.ncbi.nlm.nih.gov/pubmed/34500463
U2 - 10.1093/nar/gkab785
DO - 10.1093/nar/gkab785
M3 - Article
C2 - 34500463
AN - SCOPUS:85117363012
SN - 0305-1048
VL - 49
SP - 9906
EP - 9925
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 17
ER -