RECQ helicases and genome integrity: dissecting the function of Sgs1/BLM sumoylation in counteracting genotoxic recombination events during chromosome replication.

Eukaryotic cells control genome integrity during chromosome duplication by coordinating DNA replication with DNA recombination. A failure to integrate these processes results in genome instability and cancer as in several cancer prone diseases that are caused by mutations in checkpoint and recombination genes. The BLM disorder, resulting from mutations in a RecQ helicase gene, is characterized by recombination dysfunctions, genome instability and premature aging. The understanding of the molecular defects leading to genome instability in BLM cells is of pivotal importance for the comprehension of the mechanisms that generate genome rearrangements and that have a causative role in the genesis and the maintenance of the tumour phenotype at the somatic level. Yeast mutants altered in the Sgs1 RecQ helicase mimic the cellular defects of BLM patients. We have recently unmasked a population of evolutionary conserved sister chromatid junctions that couple chromosome replication with sister chromatid cohesion and sister chromatid-mediated recombination and replication bypass processes. These intermediates likely contribute to maintain genome integrity during DNA synthesis; however, the same structures represent a potential source for unwanted recombination events at replication forks in the absence of RecQ helicases or when cells exhibit alterations in the highly conserved Ubc9-mediated sumoylation pathway that regulates Sgs1 and Blm. These unscheduled recombination events observed in sgs1 and ubc9 mutants very well account for the chromosomal abnormalities observed in BLM cells. We aim to characterise the nature of these pathological chromosomal structures and to gain insights into the mechanisms causing their accumulation, processing and resolution. Further, we intend to characterise how the sumoylation pathway controls the function of RecQ helicases. The expected findings should help us to further focus our studies on specific eukaryotic sub-pathway(s) that either control genome stability or, rather, promote pathological chromosomal rearrangements. Further they are expected to provide relevant mechanistic insights into chromosome metabolism during DNA synthesis and, particularly, to reveal important details on how cells deal with a damaged DNA template during chromosome replication.