Universitą degli studi di Pavia
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STUDY OF MECHANISMS THAT PRESERVE EUKARYOTIC GENOME INTEGRITY DURING REPLICATION-TRANSCRIPTION CONFLICTS.
Collisions between the replisome and transcription machinery are frequent and can arrest fork progression. Stalled forks are targets for recombination enzymes that trigger unscheduled genome rearrangements. Mechanisms avoiding replication stress at transcribed genes are therefore fundamental to prevent genome instability that is a hallmark of cancer cells and certain neurodegenerative disorders.
We identified the DNA/RNA helicase Sen1 of yeast Saccharomyces cerevisiae as a crucial factor that prevent replication fork stalling and recombination-mediated processing at genes transcribed by RNA polymerase II. SEN1 gene is the ortholog of human Senataxin, which is mutated in two neurodegenerative disorders, the Ataxia with ocular motor apraxia type 2 (AOA2) and the amyotrophic lateral sclerosis type 4 (ALS4). With this study we would characterize how the Sen1-dependent pathway contribute to maintain replication fork integrity using genetic, genomic and molecular biology approaches, as it is easy applicable in the yeast model system.
Collisions between the replisome and transcription machinery are frequent and can arrest fork progression. Stalled forks are targets for recombination enzymes that trigger unscheduled genome rearrangements. Mechanisms avoiding replication stress at transcribed genes are therefore fundamental to prevent genome instability that is a hallmark of cancer cells and certain neurodegenerative disorders.
We identified the DNA/RNA helicase Sen1 of yeast Saccharomyces cerevisiae as a crucial factor that prevent replication fork stalling and recombination-mediated processing at genes transcribed by RNA polymerase II. SEN1 gene is the ortholog of human Senataxin, which is mutated in two neurodegenerative disorders, the Ataxia with ocular motor apraxia type 2 (AOA2) and the amyotrophic lateral sclerosis type 4 (ALS4). With this study we would characterize how the Sen1-dependent pathway contribute to maintain replication fork integrity using genetic, genomic and molecular biology approaches, as it is easy applicable in the yeast model system.
