Abstract
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.
Original language | English |
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Article number | e53639 |
Journal | EMBO Reports |
Volume | 23 |
Issue number | 4 |
Number of pages | 20 |
ISSN | 1469-221X |
DOIs | |
Publication status | Published - 2022 |
Bibliographical note
Publisher Copyright:© 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license
Keywords
- DNA interstrand crosslinks (ICLs)
- DNA repair
- DNA replication
- genome stability
- translesion DNA synthesis (TLS)