Endogenous Processes Underlying Clock-Like Mutational Signatures.

ABSTRACT: Wellcome Trust scientists have shown that "mutational signatures" in specific nucleotide contexts accumulate in genomes of mammalian tissues, providing clues to underlying causes of specific signatures. Analysis of cancer genomes has identified more than 50 single-base substitution (SBS) signatures, with SBS1, SBS5, and SBS40 linked to aging and present in normal tissues. SBS1 results from cytosine demethylation, whereas SBS5 and SBS40 arise from unknown endogenous mechanisms. We hypothesized that loss of fragile-site genes drives these two signatures. FHIT, located at FRA3B, is frequently deleted in cancers, and Fhit-deficient mouse tissues exhibit a mutation profile resembling human SBS5. Data mining of cancer genome sequences showed that FHIT/Fra3B was the gene loss most significantly c

SUBMITTER: Druck T 

PROVIDER: S-EPMC12820907 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature