CTC1-STN1-TEN1 controls DNA break repair pathway choice via DNA end resection blockade
Antagonistic activities of the 53BP1 axis and the tumor suppressor BRCA1-BARD1 determine whether DNA double-strand breaks (DSBs) are repaired by end joining or homologous recombination. We show that the CTC1-STN1-TEN1 (CST) complex, a central 53BP1 axis component, suppresses DNA end resection by EXO1 and the BLM-DNA2 helicase-nuclease complex but acts by distinct mechanisms in restricting these entities. Whereas BRCA1-BARD1 alleviates the CST-imposed EXO1 blockade, it has little effect on BLM-DNA2 restriction. CST mutants impaired for DNA binding or BLM-EXO1 interaction exhibit a hyper-resection phenotype and render BRCA1-deficient cells resistant to poly(ADP-ribose) polymerase (PARP) inhibitors. Our findings mechanistically define the crucial role of CST in DNA DSB repair pathway choice and have implications for understanding cancer therapy resistance stemming from dysfunction of the 53BP1 axis.
Authors
- Dipanjan Chowdhury (ORCID: https://orcid.org/0000-0001-5645-3752)
- Youngho Kwon (ORCID: https://orcid.org/0000-0002-0287-8795)
- Nozomi Tomimatsu
- Korilynn G. Kelly
- Cody M. Rogers (ORCID: https://orcid.org/0000-0001-6499-1390)
- Robert Hromas (ORCID: https://orcid.org/0000-0002-1916-6276)
- Angela M. Jasper (ORCID: https://orcid.org/0000-0002-9548-8445)
- Syed Zahid (ORCID: https://orcid.org/0000-0002-0491-3566)
- Eric C. Greene (ORCID: https://orcid.org/0000-0002-7387-824X)
- Maria Gaczyńska (ORCID: https://orcid.org/0000-0002-9033-5706)
- David S. Libich (ORCID: https://orcid.org/0000-0001-6492-2803)
- Yashpal Rawal (ORCID: https://orcid.org/0000-0001-9209-788X)
- Paweł A. Osmulski (ORCID: https://orcid.org/0000-0002-5359-9200)
- Sameer Salunkhe (ORCID: https://orcid.org/0000-0002-0008-174X)
- Shaun K. Olsen (ORCID: https://orcid.org/0000-0002-1265-7101)
- Aida Badamchi Shabestari
- Sandeep Burma (ORCID: https://orcid.org/0000-0001-7057-9845)
- Hardeep Kaur (ORCID: https://orcid.org/0000-0002-6385-8413)
- Alexander V. Mazin (ORCID: https://orcid.org/0000-0002-5430-9797)
- Kate Lawrenson (ORCID: https://orcid.org/0000-0002-6469-2515)
- Elizabeth V. Wasmuth (ORCID: https://orcid.org/0000-0003-1474-4935)
- Michelle Swift (ORCID: https://orcid.org/0000-0003-3645-1308)
- Vivek B. Raina (ORCID: https://orcid.org/0000-0003-0507-9208)
- Patrick Sung (ORCID: https://orcid.org/0000-0003-1396-9040)
- Jeffrey Wang
- Daohong Zhou (ORCID: https://orcid.org/0000-0002-2400-6461)
- Weixing Zhao (ORCID: https://orcid.org/0000-0001-5746-3696)
- James M. Daley (ORCID: https://orcid.org/0000-0002-7706-6134)
- Shuo Zhou (ORCID: https://orcid.org/0000-0001-8684-8341)
- Ajinkya S. Kawale (ORCID: https://orcid.org/0000-0001-7154-2868)
- S. Gayther
- Adam Sacks (ORCID: https://orcid.org/0000-0001-7621-3801)
Institutions
- Harvard University (US)
- The University of Texas at San Antonio Health Science Center (US)
- Columbia University Irving Medical Center (US)
- Dana-Farber Cancer Institute (US)
Publication Details
- Journal
- Science
- Published
- 2025-05-22
- DOI
- https://doi.org/10.1126/science.adt3034
- Citations
- 8
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 6.45