/ publications / [1] genomics of DNA repair

Understanding mutational processes via studying localized hypermutation 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 local chromatin organization and differential DNA repair:

Cas9 gene editing involves DNA breaks, which incur a loss of cell fitness. We find Cas9 toxicity is variable depending on the local chromatin environment, with active chromatin, such as regulatory elements or transcription elongation histone marks, predicting increased toxicity. We suggest rules to improve design of CRISPR libraries,

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

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.

"To be able to say that 'if we change our point of view in the following way ... things are simpler' is always a gain." -- John Tukey