Journal article
Highly mutagenic copying of telomeric circles promotes ALT establishment
Nature communications
04/22/2026
DOI: 10.1038/s41467-026-72032-4
PMID: 42014705
Abstract
Alternative lengthening of telomeres (ALT) is a recombination-based pathway enabling cancer cells to maintain telomeres. ALT establishment remains poorly understood due to difficulties identifying its molecular steps. Here, using Oxford Nanopore sequencing and computational modeling, we track the evolution of individual chromosome end structures during ALT establishment in yeast and delineate three molecular milestones. First, homologous recombination via break-induced replication (BIR) at telomeres and sub-telomeric regions delays senescence. Second, BIR interruption and microhomology-mediated recombination promote initial telomere extension and telomeric circle formation. Third, the final extension-critical for chromosome end stabilization-utilizes a highly mutagenic replication mechanism to copy telomeric circles. Linking these newly defined ALT milestones is Mph1, the homolog of human FANCM, which plays important roles throughout ALT establishment by disrupting BIR synthesis and promoting template switching. Our findings support a model where template switching during DNA repair synthesis drives the transitioning through the multiple steps involved in ALT establishment and progression, ultimately producing ALT survivors.
Details
- Title: Subtitle
- Highly mutagenic copying of telomeric circles promotes ALT establishment
- Creators
- Meng-Chia Tsai - The University of Texas at San Antonio Health Science CenterJacob M Wells - The University of Texas at San Antonio Health Science CenterKelley A Renninger - The University of Texas at San Antonio Health Science CenterKendra Musmaker - University of IowaRyan Pellow - University of IowaAndrey Malkov - The University of Texas at San Antonio Health Science CenterJosep M Comeron - University of IowaAnna Malkova - The University of Texas at San Antonio Health Science Center
- Resource Type
- Journal article
- Publication Details
- Nature communications
- DOI
- 10.1038/s41467-026-72032-4
- PMID
- 42014705
- NLM abbreviation
- Nat Commun
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Publisher
- Springer Nature
- Grant note
- R35GM127006 / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) RR240030 / Cancer Prevention and Research Institute of Texas (Cancer Prevention Research Institute of Texas)
- Language
- English
- Electronic publication date
- 04/22/2026
- Academic Unit
- Biology
- Record Identifier
- 9985157606602771
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