SCAI promotes error-free repair of DNA interstrand crosslinks via the Fanconi anemia pathway
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Standard
SCAI promotes error-free repair of DNA interstrand crosslinks via the Fanconi anemia pathway. / Schubert, Lisa; Hendriks, Ivo A.; Hertz, Emil P.T.; Wu, Wei; Sellés-Baiget, Selene; Hoffmann, Saskia; Viswalingam, Keerthana Stine; Gallina, Irene; Pentakota, Satyakrishna; Benedict, Bente; Johansen, Joachim; Apelt, Katja; Luijsterburg, Martijn S.; Rasmussen, Simon; Lisby, Michael; Liu, Ying; Nielsen, Michael L.; Mailand, Niels; Duxin, Julien P.
I: EMBO Reports, Bind 23, Nr. 4, e53639, 2022.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - SCAI promotes error-free repair of DNA interstrand crosslinks via the Fanconi anemia pathway
AU - Schubert, Lisa
AU - Hendriks, Ivo A.
AU - Hertz, Emil P.T.
AU - Wu, Wei
AU - Sellés-Baiget, Selene
AU - Hoffmann, Saskia
AU - Viswalingam, Keerthana Stine
AU - Gallina, Irene
AU - Pentakota, Satyakrishna
AU - Benedict, Bente
AU - Johansen, Joachim
AU - Apelt, Katja
AU - Luijsterburg, Martijn S.
AU - Rasmussen, Simon
AU - Lisby, Michael
AU - Liu, Ying
AU - Nielsen, Michael L.
AU - Mailand, Niels
AU - Duxin, Julien P.
N1 - Publisher Copyright: © 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license
PY - 2022
Y1 - 2022
N2 - DNA interstrand crosslinks (ICLs) are cytotoxic lesions that threaten genome integrity. The Fanconi anemia (FA) pathway orchestrates ICL repair during DNA replication, with ubiquitylated FANCI-FANCD2 (ID2) marking the activation step that triggers incisions on DNA to unhook the ICL. Restoration of intact DNA requires the coordinated actions of polymerase ζ (Polζ)-mediated translesion synthesis (TLS) and homologous recombination (HR). While the proteins mediating FA pathway activation have been well characterized, the effectors regulating repair pathway choice to promote error-free ICL resolution remain poorly defined. Here, we uncover an indispensable role of SCAI in ensuring error-free ICL repair upon activation of the FA pathway. We show that SCAI forms a complex with Polζ and localizes to ICLs during DNA replication. SCAI-deficient cells are exquisitely sensitive to ICL-inducing drugs and display major hallmarks of FA gene inactivation. In the absence of SCAI, HR-mediated ICL repair is defective, and breaks are instead re-ligated by polymerase θ-dependent microhomology-mediated end-joining, generating deletions spanning the ICL site and radial chromosomes. Our work establishes SCAI as an integral FA pathway component, acting at the interface between TLS and HR to promote error-free ICL repair.
AB - DNA interstrand crosslinks (ICLs) are cytotoxic lesions that threaten genome integrity. The Fanconi anemia (FA) pathway orchestrates ICL repair during DNA replication, with ubiquitylated FANCI-FANCD2 (ID2) marking the activation step that triggers incisions on DNA to unhook the ICL. Restoration of intact DNA requires the coordinated actions of polymerase ζ (Polζ)-mediated translesion synthesis (TLS) and homologous recombination (HR). While the proteins mediating FA pathway activation have been well characterized, the effectors regulating repair pathway choice to promote error-free ICL resolution remain poorly defined. Here, we uncover an indispensable role of SCAI in ensuring error-free ICL repair upon activation of the FA pathway. We show that SCAI forms a complex with Polζ and localizes to ICLs during DNA replication. SCAI-deficient cells are exquisitely sensitive to ICL-inducing drugs and display major hallmarks of FA gene inactivation. In the absence of SCAI, HR-mediated ICL repair is defective, and breaks are instead re-ligated by polymerase θ-dependent microhomology-mediated end-joining, generating deletions spanning the ICL site and radial chromosomes. Our work establishes SCAI as an integral FA pathway component, acting at the interface between TLS and HR to promote error-free ICL repair.
KW - DNA interstrand crosslinks (ICLs)
KW - DNA repair
KW - DNA replication
KW - genome stability
KW - translesion DNA synthesis (TLS)
U2 - 10.15252/embr.202153639
DO - 10.15252/embr.202153639
M3 - Journal article
C2 - 35156773
AN - SCOPUS:85124540448
VL - 23
JO - E M B O Reports
JF - E M B O Reports
SN - 1469-221X
IS - 4
M1 - e53639
ER -
ID: 297953508