/ publications / [1] genomics of DNA repair

Dissecting mutational processes via localized hypermutation (mutation clustering) patterns:

We classified patterns of clustered mutagenesis in tumor genomes, identifying a new pattern: nonrecurrent, diffuse hypermutation (omikli). // This mechanism occurs independently of the known focal hypermutation (kataegis), and is associated with DNA repair activity which can provide the single-stranded DNA substrate needed by APOBEC3A enzyme.

Mutation clusters in cancer genomes provide fingerprints of mutagenic mechanisms // Error-free mismatch repair lowers the mutation rate in H3K36me3-marked active genes // Error-prone repair using POLH also targets H3K36me3, contributing driver mutations // UV and alcohol increase error-prone repair, targeting mutations toward active genes.

Links between chromatin organization and differential DNA repair:

Somatic mutation rates exhibit tissue-specificity coupled to regional changes in DNA replication timing and gene expression. A temporal deconvolution of mutational signatures in microsatellite-instable tumors of the colon, stomach and uterus demonstrates that post-replicative MMR is the cause of the megabase-scale mutation rate variability in the human genome.

Loss of activity of a H3K9 methyltransferase doesn't alter the global landscape of mutations in chemically induced tumors // DNA replication time and H3K36me3 histone mark, not chromatin accesibility, are determinants of mutation rates // H3K9me2/3-depleted tumors are genomically instable, and after a prolonged latency, very agressive

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