Soriano, I;
Vazquez, E;
De Leon, N;
Bertrand, S;
Heitzer, E;
Toumazou, S;
Bo, Z;
Palles, C;
Pai, C-C;
Humphrey, TC;
et al.
Soriano, I; Vazquez, E; De Leon, N; Bertrand, S; Heitzer, E; Toumazou, S; Bo, Z; Palles, C; Pai, C-C; Humphrey, TC; Tomlinson, I; Cotterill, S; Kearsey, SE
(2021)
Expression of the cancer-associated DNA polymerase ε P286R in fission yeast leads to translesion synthesis polymerase dependent hypermutation and defective DNA replication.
PLoS Genet, 17 (7).
e1009526.
ISSN 1553-7404
https://doi.org/10.1371/journal.pgen.1009526
SGUL Authors: Cotterill, Susan Margaret
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Abstract
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.
Item Type: | Article | |||||||||
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Additional Information: | Copyright: © 2021 Soriano et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | |||||||||
Keywords: | 0604 Genetics, Developmental Biology | |||||||||
SGUL Research Institute / Research Centre: | Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) | |||||||||
Journal or Publication Title: | PLoS Genet | |||||||||
ISSN: | 1553-7404 | |||||||||
Language: | eng | |||||||||
Dates: |
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Publisher License: | Creative Commons: Attribution 4.0 | |||||||||
Projects: |
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PubMed ID: | 34228709 | |||||||||
Web of Science ID: | WOS:000674292800005 | |||||||||
Go to PubMed abstract | ||||||||||
URI: | https://openaccess.sgul.ac.uk/id/eprint/113593 | |||||||||
Publisher's version: | https://doi.org/10.1371/journal.pgen.1009526 |
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