The hereditary N363K POLE exonuclease mutant extends PPAP tumor spectrum to glioblastomas by causing DNA damage and aneuploidy in addition to increased mismatch mutagenicity.

ABSTRACT: The exonuclease domain of DNA polymerases epsilon's catalytic subunit (POLE) removes misincorporated nucleotides, called proofreading. POLE-exonuclease mutations cause colorectal- and endometrial cancers with an extreme burden of single nucleotide substitutions. We recently reported that particularly the hereditary POLE exonuclease mutation N363K predisposes in addition to aggressive giant cell glioblastomas. We knocked-in this mutation homozygously into human cell lines and compared its properties to knock-ins of the likewise hereditary POLE L424V mutation and to a complete proofreading-inactivating mutation (exo-null). We found that N363K cells have higher mutation rates as both L424V- or exo-null mutant cells. In contrast to L424V cells, N363K cells expose a growth defect, replication s

SUBMITTER: Labrousse G 

PROVIDER: S-EPMC10006997 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature