Hypermutability of damaged single-strand DNA formed at double-strand breaks and uncapped telomeres in yeast Saccharomyces cerevisiae.

The major DNA repair pathways operate on damage in double-strand DNA because they use the intact strand as a template after damage removal. Therefore, lesions in transient single-strand stretches of chromosomal DNA are expected to be especially threatening to genome stability. To test this hypothesi...

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Main Authors:	Yong Yang, Joan Sterling, Francesca Storici, Michael A Resnick, Dmitry A Gordenin
Format:	article
Language:	EN
Published:	Public Library of Science (PLoS) 2008
Subjects:	Genetics QH426-470
Online Access:	https://doaj.org/article/fba5064b3f7f427dad3cfef0c0f474c7
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spelling	oai:doaj.org-article:fba5064b3f7f427dad3cfef0c0f474c72021-12-02T20:03:11ZHypermutability of damaged single-strand DNA formed at double-strand breaks and uncapped telomeres in yeast Saccharomyces cerevisiae.1553-73901553-740410.1371/journal.pgen.1000264https://doaj.org/article/fba5064b3f7f427dad3cfef0c0f474c72008-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19023402/pdf/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404The major DNA repair pathways operate on damage in double-strand DNA because they use the intact strand as a template after damage removal. Therefore, lesions in transient single-strand stretches of chromosomal DNA are expected to be especially threatening to genome stability. To test this hypothesis, we designed systems in budding yeast that could generate many kilobases of persistent single-strand DNA next to double-strand breaks or uncapped telomeres. The systems allowed controlled restoration to the double-strand state after applying DNA damage. We found that lesions induced by UV-light and methyl methanesulfonate can be tolerated in long single-strand regions and are hypermutagenic. The hypermutability required PCNA monoubiquitination and was largely attributable to translesion synthesis by the error-prone DNA polymerase zeta. In support of multiple lesions in single-strand DNA being a source of hypermutability, analysis of the UV-induced mutants revealed strong strand-specific bias and unexpectedly high frequency of alleles with widely separated multiple mutations scattered over several kilobases. Hypermutability and multiple mutations associated with lesions in transient stretches of long single-strand DNA may be a source of carcinogenesis and provide selective advantage in adaptive evolution.Yong YangJoan SterlingFrancesca StoriciMichael A ResnickDmitry A GordeninPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 4, Iss 11, p e1000264 (2008)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Yong Yang Joan Sterling Francesca Storici Michael A Resnick Dmitry A Gordenin Hypermutability of damaged single-strand DNA formed at double-strand breaks and uncapped telomeres in yeast Saccharomyces cerevisiae.
description	The major DNA repair pathways operate on damage in double-strand DNA because they use the intact strand as a template after damage removal. Therefore, lesions in transient single-strand stretches of chromosomal DNA are expected to be especially threatening to genome stability. To test this hypothesis, we designed systems in budding yeast that could generate many kilobases of persistent single-strand DNA next to double-strand breaks or uncapped telomeres. The systems allowed controlled restoration to the double-strand state after applying DNA damage. We found that lesions induced by UV-light and methyl methanesulfonate can be tolerated in long single-strand regions and are hypermutagenic. The hypermutability required PCNA monoubiquitination and was largely attributable to translesion synthesis by the error-prone DNA polymerase zeta. In support of multiple lesions in single-strand DNA being a source of hypermutability, analysis of the UV-induced mutants revealed strong strand-specific bias and unexpectedly high frequency of alleles with widely separated multiple mutations scattered over several kilobases. Hypermutability and multiple mutations associated with lesions in transient stretches of long single-strand DNA may be a source of carcinogenesis and provide selective advantage in adaptive evolution.
format	article
author	Yong Yang Joan Sterling Francesca Storici Michael A Resnick Dmitry A Gordenin
author_facet	Yong Yang Joan Sterling Francesca Storici Michael A Resnick Dmitry A Gordenin
author_sort	Yong Yang
title	Hypermutability of damaged single-strand DNA formed at double-strand breaks and uncapped telomeres in yeast Saccharomyces cerevisiae.
title_short	Hypermutability of damaged single-strand DNA formed at double-strand breaks and uncapped telomeres in yeast Saccharomyces cerevisiae.
title_full	Hypermutability of damaged single-strand DNA formed at double-strand breaks and uncapped telomeres in yeast Saccharomyces cerevisiae.
title_fullStr	Hypermutability of damaged single-strand DNA formed at double-strand breaks and uncapped telomeres in yeast Saccharomyces cerevisiae.
title_full_unstemmed	Hypermutability of damaged single-strand DNA formed at double-strand breaks and uncapped telomeres in yeast Saccharomyces cerevisiae.
title_sort	hypermutability of damaged single-strand dna formed at double-strand breaks and uncapped telomeres in yeast saccharomyces cerevisiae.
publisher	Public Library of Science (PLoS)
publishDate	2008
url	https://doaj.org/article/fba5064b3f7f427dad3cfef0c0f474c7
work_keys_str_mv	AT yongyang hypermutabilityofdamagedsinglestranddnaformedatdoublestrandbreaksanduncappedtelomeresinyeastsaccharomycescerevisiae AT joansterling hypermutabilityofdamagedsinglestranddnaformedatdoublestrandbreaksanduncappedtelomeresinyeastsaccharomycescerevisiae AT francescastorici hypermutabilityofdamagedsinglestranddnaformedatdoublestrandbreaksanduncappedtelomeresinyeastsaccharomycescerevisiae AT michaelaresnick hypermutabilityofdamagedsinglestranddnaformedatdoublestrandbreaksanduncappedtelomeresinyeastsaccharomycescerevisiae AT dmitryagordenin hypermutabilityofdamagedsinglestranddnaformedatdoublestrandbreaksanduncappedtelomeresinyeastsaccharomycescerevisiae
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Hypermutability of damaged single-strand DNA formed at double-strand breaks and uncapped telomeres in yeast Saccharomyces cerevisiae.

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