My current research is dedicated to translating recent advancements in understanding DNA repair in model organisms into elucidating the causes of human disease. It has long been suspected that cancer is a result of both genetic predisposition and adverse environmental factors but only now modern sequencing technologies enabled us to obtain a detailed view of the molecular processes underlying cancer pathogenesis. Recent research in Anton Gartner’s laboratory employed Caenorhabditis elegans whole-genome sequencing to characterize mutational signatures resulting from DNA repair deficiencies, treatment with genotoxic agents, or a combination of both.
In many instances, mutational signatures in worms closely resemble those in humans reflecting the high degree of conservation of DNA repair pathways. Interestingly, in certain cases, worms’ signatures display higher similarity with computed mutational spectra of human cancers than experimental signatures observed in certain human cell lines.
However, the occasional discrepancies that had been observed between C. elegans and humans or among different human cell lines are equally insightful, since they highlight the differences in genotoxin metabolism or predominance of different DNA repair pathways.
We now plan to build upon the characterization of spontaneous and induced mutagenesis in C. elegans and expand our experimental efforts to human cells. The genotype/genotoxin combinations, which produced the most remarkable effects in the worms, will be evaluated in an isogenic set of human cell lines using genomic sequencing as well as cell biology techniques.
In a living cell DNA repair takes place not on naked DNA but on structured chromatin, which is organized by nucleosomes and then further assembled into large dynamic loops maintained by cohesin rings. Recent research indicates that chromatin loops function as “natural” modules in DNA repair. For example, DNA topoisomerases II localize at the base of the loops, phosphorylated histone H2AX spreads from the site of the DNA double-strand break to cover the entire loop and the DNA break itself will have to be drawn to the site of cohesion to establish contact with the intact sister chromatid during homologous recombination repair. In our section, we started to investigate how chromosomal structure influences DNA repair processes and hope that many exciting discoveries will soon be made in this emerging field of research.