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SCAI promotes error‐free repair of DNA interstrand crosslinks via the Fanconi anemia pathway
Author(s) -
Schubert Lisa,
Hendriks Ivo A,
Hertz Emil P T,
Wu Wei,
SellésBaiget 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
Publication year - 2022
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202153639
Subject(s) - fanconi anemia , fancd2 , dna repair , dna replication , homologous recombination , dna , biology , dna polymerase , dna damage , genome instability , microbiology and biotechnology , genetics , chemistry
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.