Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Soriano, I; Vazquez, E; De, Leon, N; Bertrand, S; Heitzer, E; Toumazou, S; Bo, Z; Palles, C; Pai, CC; Humphrey, TC; Tomlinson, I; Cotterill, S; Kearsey, SE.
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. 2021; 17(7): e1009526
Doi: 10.1371/journal.pgen.1009526
[OPEN ACCESS]
Web of Science
PubMed
FullText
FullText_MUG
- Co-Autor*innen der Med Uni Graz
- Heitzer Ellen
- Altmetrics:
- Dimensions Citations:
- Plum Analytics:
- Scite (citation analytics):
- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Checkpoint Kinase 2 - genetics
- DNA Helicases - genetics
- DNA Polymerase II - genetics, metabolism
- DNA Replication - administration & dosage
- Genome, Fungal - administration & dosage
- Humans - administration & dosage
- Mutation - administration & dosage
- Neoplasms - genetics
- Poly-ADP-Ribose Binding Proteins - genetics
- S Phase - genetics
- Schizosaccharomyces - genetics, metabolism
- Schizosaccharomyces pombe Proteins - genetics, metabolism