Expression of the cancer-associated DNA polymerase ε P286R in fission yeast leads to translesion synthesis polymerase dependent hypermutation and defective DNA replication.

Somatic and germline mutations in the proofreading domain of the replicative DNA polymerase ε (POLE-exonuclease domain mutations, POLE-EDMs) are frequently found in colorectal and endometrial cancers and, occasionally, in other tumours. POLE-associated cancers typically display hypermutation, and a...

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Autores principales:	Ignacio Soriano, Enrique Vazquez, Nagore De Leon, Sibyl Bertrand, Ellen Heitzer, Sophia Toumazou, Zhihan Bo, Claire Palles, Chen-Chun Pai, Timothy C Humphrey, Ian Tomlinson, Sue Cotterill, Stephen E Kearsey
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/41959734e90f44aea3b54eb5d11908ec
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spelling	oai:doaj.org-article:41959734e90f44aea3b54eb5d11908ec2021-12-02T20:02:46ZExpression of the cancer-associated DNA polymerase ε P286R in fission yeast leads to translesion synthesis polymerase dependent hypermutation and defective DNA replication.1553-73901553-740410.1371/journal.pgen.1009526https://doaj.org/article/41959734e90f44aea3b54eb5d11908ec2021-07-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009526https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Somatic and germline mutations in the proofreading domain of the replicative DNA polymerase ε (POLE-exonuclease domain mutations, POLE-EDMs) are frequently found in colorectal and endometrial cancers and, occasionally, in other tumours. POLE-associated cancers typically display hypermutation, and a unique mutational signature, with a predominance of C > A transversions in the context TCT and C > T transitions in the context TCG. To understand better the contribution of hypermutagenesis to tumour development, we have modelled the most recurrent POLE-EDM (POLE-P286R) in Schizosaccharomyces pombe. Whole-genome sequencing analysis revealed that the corresponding pol2-P287R allele also has a strong mutator effect in vivo, with a high frequency of base substitutions and relatively few indel mutations. The mutations are equally distributed across different genomic regions, but in the immediate vicinity there is an asymmetry in AT frequency. The most abundant base-pair changes are TCT > TAT transversions and, in contrast to human mutations, TCG > TTG transitions are not elevated, likely due to the absence of cytosine methylation in fission yeast. The pol2-P287R variant has an increased sensitivity to elevated dNTP levels and DNA damaging agents, and shows reduced viability on depletion of the Pfh1 helicase. In addition, S phase is aberrant and RPA foci are elevated, suggestive of ssDNA or DNA damage, and the pol2-P287R mutation is synthetically lethal with rad3 inactivation, indicative of checkpoint activation. Significantly, deletion of genes encoding some translesion synthesis polymerases, most notably Pol κ, partially suppresses pol2-P287R hypermutation, indicating that polymerase switching contributes to this phenotype.Ignacio SorianoEnrique VazquezNagore De LeonSibyl BertrandEllen HeitzerSophia ToumazouZhihan BoClaire PallesChen-Chun PaiTimothy C HumphreyIan TomlinsonSue CotterillStephen E KearseyPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 7, p e1009526 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Ignacio Soriano Enrique Vazquez Nagore De Leon Sibyl Bertrand Ellen Heitzer Sophia Toumazou Zhihan Bo Claire Palles Chen-Chun Pai Timothy C Humphrey Ian Tomlinson Sue Cotterill Stephen E Kearsey Expression of the cancer-associated DNA polymerase ε P286R in fission yeast leads to translesion synthesis polymerase dependent hypermutation and defective DNA replication.
description	Somatic and germline mutations in the proofreading domain of the replicative DNA polymerase ε (POLE-exonuclease domain mutations, POLE-EDMs) are frequently found in colorectal and endometrial cancers and, occasionally, in other tumours. POLE-associated cancers typically display hypermutation, and a unique mutational signature, with a predominance of C > A transversions in the context TCT and C > T transitions in the context TCG. To understand better the contribution of hypermutagenesis to tumour development, we have modelled the most recurrent POLE-EDM (POLE-P286R) in Schizosaccharomyces pombe. Whole-genome sequencing analysis revealed that the corresponding pol2-P287R allele also has a strong mutator effect in vivo, with a high frequency of base substitutions and relatively few indel mutations. The mutations are equally distributed across different genomic regions, but in the immediate vicinity there is an asymmetry in AT frequency. The most abundant base-pair changes are TCT > TAT transversions and, in contrast to human mutations, TCG > TTG transitions are not elevated, likely due to the absence of cytosine methylation in fission yeast. The pol2-P287R variant has an increased sensitivity to elevated dNTP levels and DNA damaging agents, and shows reduced viability on depletion of the Pfh1 helicase. In addition, S phase is aberrant and RPA foci are elevated, suggestive of ssDNA or DNA damage, and the pol2-P287R mutation is synthetically lethal with rad3 inactivation, indicative of checkpoint activation. Significantly, deletion of genes encoding some translesion synthesis polymerases, most notably Pol κ, partially suppresses pol2-P287R hypermutation, indicating that polymerase switching contributes to this phenotype.
format	article
author	Ignacio Soriano Enrique Vazquez Nagore De Leon Sibyl Bertrand Ellen Heitzer Sophia Toumazou Zhihan Bo Claire Palles Chen-Chun Pai Timothy C Humphrey Ian Tomlinson Sue Cotterill Stephen E Kearsey
author_facet	Ignacio Soriano Enrique Vazquez Nagore De Leon Sibyl Bertrand Ellen Heitzer Sophia Toumazou Zhihan Bo Claire Palles Chen-Chun Pai Timothy C Humphrey Ian Tomlinson Sue Cotterill Stephen E Kearsey
author_sort	Ignacio Soriano
title	Expression of the cancer-associated DNA polymerase ε P286R in fission yeast leads to translesion synthesis polymerase dependent hypermutation and defective DNA replication.
title_short	Expression of the cancer-associated DNA polymerase ε P286R in fission yeast leads to translesion synthesis polymerase dependent hypermutation and defective DNA replication.
title_full	Expression of the cancer-associated DNA polymerase ε P286R in fission yeast leads to translesion synthesis polymerase dependent hypermutation and defective DNA replication.
title_fullStr	Expression of the cancer-associated DNA polymerase ε P286R in fission yeast leads to translesion synthesis polymerase dependent hypermutation and defective DNA replication.
title_full_unstemmed	Expression of the cancer-associated DNA polymerase ε P286R in fission yeast leads to translesion synthesis polymerase dependent hypermutation and defective DNA replication.
title_sort	expression of the cancer-associated dna polymerase ε p286r in fission yeast leads to translesion synthesis polymerase dependent hypermutation and defective dna replication.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/41959734e90f44aea3b54eb5d11908ec
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Expression of the cancer-associated DNA polymerase ε P286R in fission yeast leads to translesion synthesis polymerase dependent hypermutation and defective DNA replication.

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