Journal article
CST complex promotes second-strand synthesis in break-induced replication
Nature structural & molecular biology, Vol.33(7), pp.1075-1085
07/13/2026
DOI: 10.1038/s41594-026-01832-5
PMID: 42443617
Abstract
Break-induced DNA replication (BIR) is a highly mutagenic recombination pathway used by eukaryotic cells to repair single-ended DNA breaks, mediate mitotic DNA synthesis and promote telomerase-independent telomere maintenance in certain cancers. Leading-strand synthesis in BIR is mediated by a migrating D-loop driven by DNA polymerase δ and Pif1 helicase but the mechanism of second-strand synthesis has remained poorly understood. Here we demonstrate that in yeast cells lacking Cdc13–Stn1–Ten1 (CST complex), the early steps of BIR including 5′ strand resection, D-loop formation and first-strand synthesis proceed normally. However, second-strand synthesis is impaired, implicating CST in this critical BIR step. The function of CST in BIR is conserved in human cells. Using biochemical reconstitution with DNA substrates mimicking BIR intermediates, we demonstrate that yeast CST promotes second-strand synthesis by enhancing DNA polymerase α–primase activity. Our findings provide mechanistic insight into how BIR supports long-tract DNA synthesis independently of the S-phase replisome.
Here Thakre, Wang and Liu and colleagues show that the Cdc13–Stn1–Ten1 complex helps cells to repair broken DNA by enabling synthesis of the second DNA strand during break-induced replication, a process important for genome stability and telomere maintenance in some cancers.
Details
- Title: Subtitle
- CST complex promotes second-strand synthesis in break-induced replication
- Creators
- Pilendra Thakre - Baylor College of MedicineJeff Wang - The University of Texas at San Antonio Health Science CenterLiping Liu - The University of Texas at San Antonio Health Science CenterSameer Shah - Scripps Research InstituteZhenxin Yan - Baylor College of MedicineNhung Pham - Baylor College of MedicineMeng-Chia Tsai - The University of Texas at San Antonio Health Science CenterYuqin Zhao - Scripps Research InstituteCody M. Rogers - The University of Texas at San Antonio Health Science CenterZhitong Feng - Indiana University BloomingtonHengyao Niu - Indiana University BloomingtonYoungho Kwon - The University of Texas at San Antonio Health Science CenterXiaohua Wu - Scripps Research InstituteAnna Malkova - The University of Texas at San Antonio Health Science CenterPatrick Sung - The University of Texas at San Antonio Health Science CenterGrzegorz Ira - Baylor College of Medicine
- Resource Type
- Journal article
- Publication Details
- Nature structural & molecular biology, Vol.33(7), pp.1075-1085
- DOI
- 10.1038/s41594-026-01832-5
- PMID
- 42443617
- NLM abbreviation
- Nat Struct Mol Biol
- ISSN
- 1545-9993
- eISSN
- 1545-9985
- Publisher
- Nature Publishing Group US
- Number of pages
- 11
- Grant note
- National Institutes of Health (NIH): R35GM158251, R01GM125650 NIH: R01CA168635, R01ES007061, R35CA241801, P01CA275717, AQ-0012 Cancer Prevention and Research Institute of Texas: RR240030 American Cancer Society postdoctoral fellowship: PF-22-034-01-DMC, R35GM152207 American Cancer Society Research Scholar Award: RSG-21-013-01-DMC
P.T., Z.Y., N.P. and G.I. disclose support for the research presented in this work from the National Institutes of Health (NIH) grants R35GM158251 and R01GM125650 to G.I. J.W. was supported by NIH grants T32GM145432 and T32CA148724. L.L., M.-C.T. and A.M. disclose support from Cancer Prevention and Research Institute of Texas grant RR240030 and NIH grant R35GM127006 to A.M. S.S., Y.Z. and X.W. disclose support from NIH grant R35GM141868 to X.W. C.M.R. was supported by an American Cancer Society postdoctoral fellowship PF-22-034-01-DMC. Z.F. and H.N. disclose support from NIH grant R35GM152207 and an American Cancer Society Research Scholar Award RSG-21-013-01-DMC to H.N. Y.K. discloses support from NIH grants R50CA265315 and P01CA275717 to Y.K. and P.S. P.S. discloses support from NIH grants R01CA168635, R01ES007061, R35CA241801 and P01CA275717 and is the holder of the Robert A. Welch Distinguished Chair in Chemistry (AQ-0012).
- Language
- English
- Date published
- 07/13/2026
- Academic Unit
- Biology
- Record Identifier
- 9985183130402771
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