Journal article
Shieldin and CST co-orchestrate DNA polymerase-dependent tailed-end joining reactions independently of 53BP1-governed repair pathway choice
- Abstract:
- Tumor suppressor p53-binding protein 1 (53BP1) regulates DNA end joining in lymphocytes, diversifying immune antigen receptors. This involves nucleosome-bound 53BP1 at DNA double-stranded breaks (DSBs) recruiting Rap1-interacting factor 1 homolog (RIF1) and shieldin, a poorly understood DNA-binding complex. The 53BP1–RIF1–shieldin axis is pathological in BRCA1-mutated cancers, blocking homologous recombination (HR) and driving illegitimate nonhomologous end joining (NHEJ). However, how this axis regulates DNA end joining and HR suppression remains unresolved. We investigated shieldin and its interplay with the Ctc1–Stn1–Ten1 (CST) complex, which was recently implicated downstream of 53BP1. Immunophenotypically, mice lacking shieldin or CST are equivalent, with class-switch recombination coreliant on both complexes. Ataxia-telangiectasia mutated kinase-dependent DNA damage signaling underpins this cooperation, inducing physical interactions between these complexes that reveal shieldin as a DSB-responsive CST adaptor. Furthermore, DNA polymerase ζ functions downstream of shieldin, establishing DNA fill-in synthesis as the physiological function of shieldin–CST. Lastly, we demonstrate that 53BP1 suppresses HR and promotes NHEJ in BRCA1-deficient mice and cells independently of shieldin. These findings showcase the versatility of the 53BP1 pathway, achieved through the collaboration of chromatin-bound 53BP1 complexes and DNA end-processing effector proteins.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 9.9MB, Terms of use)
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- Publisher copy:
- 10.1038/s41594-024-01381-9
Authors
+ Cancer Research UK
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- Funder identifier:
- https://ror.org/054225q67
- Grant:
- RCCSCF-Nov21\100004
- 19270
+ Medical Research Council
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- Funder identifier:
- https://ror.org/03x94j517
- Grant:
- MR/R017549/1
- MR/M009971/1
+ Lister Institute of Preventive Medicine
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- Funder identifier:
- https://ror.org/03356n642
- Publisher:
- Springer Nature
- Journal:
- Nature Structural and Molecular Biology More from this journal
- Volume:
- 32
- Issue:
- 1
- Pages:
- 86–97
- Publication date:
- 2024-09-03
- Acceptance date:
- 2024-08-01
- DOI:
- EISSN:
-
1545-9985
- ISSN:
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1545-9993
- Language:
-
English
- Pubs id:
-
2022024
- Local pid:
-
pubs:2022024
- Deposit date:
-
2024-08-16
Terms of use
- Copyright holder:
- King et al
- Copyright date:
- 2024
- Rights statement:
- © 2024 The Authors. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
- Licence:
- CC Attribution (CC BY)
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