Journal article
A unified alternative telomere-lengthening pathway in yeast survivor cells
Molecular cell, Vol.81(8), pp.1816-1829.e5
04/15/2021
DOI: 10.1016/j.molcel.2021.02.004
PMCID: PMC8052312
PMID: 33639094
Abstract
Alternative lengthening of telomeres (ALT) is a recombination process that maintains telomeres in the absence of telomerase and helps cancer cells to survive. Yeast has been used as a robust model of ALT; however, the inability to determine the frequency and structure of ALT survivors hinders understanding of the ALT mechanism. Here, using population and molecular genetics approaches, we overcome these problems and demonstrate that contrary to the current view, both RAD51-dependent and RAD51-independent mechanisms are required for a unified ALT survivor pathway. This conclusion is based on the calculation of ALT frequencies, as well as on ultra-long sequencing of ALT products that revealed hybrid sequences containing features attributed to both recombination pathways. Sequencing of ALT intermediates demonstrates that recombination begins with Rad51-mediated strand invasion to form DNA substrates that are matured by a Rad51-independent ssDNA annealing pathway. A similar unified ALT pathway may operate in other organisms, including humans.
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•ALT frequency in yeast was identified by using a population genetics approach•Ultra-long sequencing identifies hybrid type I/type II ALT survivors in yeast•Rad51 and Rad59 define two consecutive steps in the unified ALT pathway in yeast•Rad51 promotes the formation of ALT precursors that become survivors by Rad59/Rad52
Alternative lengthening of telomeres (ALT) was believed to proceed in yeast via two separate pathways. Kockler et al. combined population genetic principles and ultra-long sequencing to determine the frequency and molecular structure identity of ALT survivors, which revealed a unified pathway that includes both Rad51-dependent and Rad51-independent steps.
Details
- Title: Subtitle
- A unified alternative telomere-lengthening pathway in yeast survivor cells
- Creators
- Zachary W Kockler - Department of Biology, University of Iowa, Iowa City, IA 52245, USAJosep M Comeron - Department of Biology, University of Iowa, Iowa City, IA 52245, USAAnna Malkova - Department of Biology, University of Iowa, Iowa City, IA 52245, USA
- Resource Type
- Journal article
- Publication Details
- Molecular cell, Vol.81(8), pp.1816-1829.e5
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.molcel.2021.02.004
- PMID
- 33639094
- PMCID
- PMC8052312
- ISSN
- 1097-2765
- eISSN
- 1097-4164
- Grant note
- DOI: 10.13039/100000066, name: National Institute of Environmental Health Sciences; DOI: 10.13039/100000057, name: National Institute of General Medical Sciences
- Language
- English
- Date published
- 04/15/2021
- Academic Unit
- Biology
- Record Identifier
- 9984217532702771
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