Final Activity Report Summary - REPLI-HEM (Mechanisms promoting the formation and migration of cruciform sister chromatid junctions during chromosome replication.)
We have used the budding yeast Saccharomyces cerevisiae as a model system to study factors influencing genome stability. The maintenance of genome integrity is pivotal to prevent cancer. Chromosomal rearrangements can result from unrepaired DNA lesions or from aberrant DNA repair events, often associated with recombination.
We have studied the role of a series of proteins involved in the metabolism of recombination structures arising during chromosome replication. In particular we have extensively characterised the yeast protein HMO1 that belongs to the high mobility group (HMG) family of proteins; mutations in the human orthologs of this protein have been found in several tumour types.
We have found that HMO1 is involved in the formation and/or stabilisation of certain recombinogenic structures which are resolved by SGS1, a member of the RecQ helicase family. Mutations in human orthologs of SGS1, BLM and WRN helicases, cause the cancer-prone Bloom and Werner syndromes; in addition we also found a possible regulation of HMO1 DNA binding through sumoylation. We also found that deletion of HMO1 results in a delayed and weakened activation of checkpoint; whether this is due to a direct participation of HMO1 in the checkpoint signalling cascade or to an indirect effect is still to be elucidated.
These results altogether allow us to envisage a scenario in which HMO1 would work in the response to DNA damage at two levels, maybe related among them. First, by ensuring an efficient activation of the checkpoint response. Second, facilitating chromosome replication across DNA lesions.
We have studied the role of a series of proteins involved in the metabolism of recombination structures arising during chromosome replication. In particular we have extensively characterised the yeast protein HMO1 that belongs to the high mobility group (HMG) family of proteins; mutations in the human orthologs of this protein have been found in several tumour types.
We have found that HMO1 is involved in the formation and/or stabilisation of certain recombinogenic structures which are resolved by SGS1, a member of the RecQ helicase family. Mutations in human orthologs of SGS1, BLM and WRN helicases, cause the cancer-prone Bloom and Werner syndromes; in addition we also found a possible regulation of HMO1 DNA binding through sumoylation. We also found that deletion of HMO1 results in a delayed and weakened activation of checkpoint; whether this is due to a direct participation of HMO1 in the checkpoint signalling cascade or to an indirect effect is still to be elucidated.
These results altogether allow us to envisage a scenario in which HMO1 would work in the response to DNA damage at two levels, maybe related among them. First, by ensuring an efficient activation of the checkpoint response. Second, facilitating chromosome replication across DNA lesions.