SCAI promotes error-free repair of DNA interstrand crosslinks via the Fanconi anemia pathway
© 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:23 |
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| Enthalten in: |
EMBO reports - 23(2022), 4 vom: 05. Apr., Seite e53639 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Schubert, Lisa [VerfasserIn] |
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| Links: |
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| Themen: |
9007-49-2 |
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| Anmerkungen: |
Date Completed 07.04.2022 Date Revised 14.05.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.15252/embr.202153639 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM336888945 |
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| 245 | 1 | 0 | |a SCAI promotes error-free repair of DNA interstrand crosslinks via the Fanconi anemia pathway |
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| 520 | |a © 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a DNA interstrand crosslinks (ICLs) | |
| 650 | 4 | |a DNA repair | |
| 650 | 4 | |a DNA replication | |
| 650 | 4 | |a genome stability | |
| 650 | 4 | |a translesion DNA synthesis (TLS) | |
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| 650 | 7 | |a 9007-49-2 |2 NLM | |
| 700 | 1 | |a Hendriks, Ivo A |e verfasserin |4 aut | |
| 700 | 1 | |a Hertz, Emil P T |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Sellés-Baiget, Selene |e verfasserin |4 aut | |
| 700 | 1 | |a Hoffmann, Saskia |e verfasserin |4 aut | |
| 700 | 1 | |a Viswalingam, Keerthana Stine |e verfasserin |4 aut | |
| 700 | 1 | |a Gallina, Irene |e verfasserin |4 aut | |
| 700 | 1 | |a Pentakota, Satyakrishna |e verfasserin |4 aut | |
| 700 | 1 | |a Benedict, Bente |e verfasserin |4 aut | |
| 700 | 1 | |a Johansen, Joachim |e verfasserin |4 aut | |
| 700 | 1 | |a Apelt, Katja |e verfasserin |4 aut | |
| 700 | 1 | |a Luijsterburg, Martijn S |e verfasserin |4 aut | |
| 700 | 1 | |a Rasmussen, Simon |e verfasserin |4 aut | |
| 700 | 1 | |a Lisby, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Nielsen, Michael L |e verfasserin |4 aut | |
| 700 | 1 | |a Mailand, Niels |e verfasserin |4 aut | |
| 700 | 1 | |a Duxin, Julien P |e verfasserin |4 aut | |
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