SCAI promotes error‐free repair of DNA interstrand crosslinks via the Fanconi anemia pathway

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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.

Location: Deutsche Nationalbibliothek Frankfurt am Main

Extent: Online-Ressource

Language: Englisch

Bibliographic citation: SCAI promotes error‐free repair of DNA interstrand crosslinks via the Fanconi anemia pathway ; day:14 ; month:02 ; year:2022 ; extent:20
EMBO reports / European Molecular Biology Organization ; (14.02.2022) (gesamt 20)

Creator: 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.

DOI: 10.15252/embr.202153639

URN: urn:nbn:de:101:1-2022021414080033232098

Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.

Last update: 15.08.2025, 7:24 AM CEST

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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.

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SCAI promotes error‐free repair of DNA interstrand crosslinks via the Fanconi anemia pathway

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