Embedded Files
Analyses of local hypermutation patterns to study DNA repair:
DNA mismatch repair promotes APOBEC3-mediated diffuse hypermutation in human cancers. D Mas-Ponte, F Supek (2020) Nature Genetics.
We classified patterns of clustered mutagenesis in tumor genomes, identifying a new pattern: nonrecurrent, diffuse hypermutation "fog" 🌫️ (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.
Clustered Mutation Signatures Reveal that Error-Prone DNA Repair Targets Mutations to Active Genes. F Supek, B Lehner (2017) Cell.
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 DNA repair activity:
Cell cycle gene alterations associate with a redistribution of mutation risk across chromosomal domains in human cancers. M Salvadores, F Supek (2024) Nature Cancer.
Regional mutation risk varies between individual tumors in a manner independent of cell type; we identified three signatures of domain-scale mutagenesis in >4,000 tumor genomes. // Regional mutagenesis is associated with loss of activity of the tumor-suppressor genes RB1 and TP53, consistent with their roles in cell cycle control.
🔥 covered in a "News and views" text by Hu & De 👉 read here *
TP53-dependent toxicity of CRISPR/Cas9 cuts is differential across genomic loci and can confound genetic screening. M Alvarez, J Biayna, F Supek (2022) Nature Communications.
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 G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours. A Avgustinova*, A Symeonidi [...] F Supek*, S Aznar-Benitah* (2018) Nature Cell Biology. (*corresponding authors)
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
"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
Page updated
Google Sites
Report abuse