Molecular characterization of SEN1/SETX-controlled pathways defective in the AOA2 and ASL4 neurodegenerative syndromes.

Mutations in Senataxin gene, which encodes for a evolutionarily conserved DNA/RNA helicase, cause two severe neurodegenerative disorders, the Ataxia with oculomotor apraxia type 2 (AOA2) and juvenile Amyotrophic lateral sclerosis type 4 (ALS4). Combining genomic and genetic approaches together with the analysis of replication intermediates, we unmasked a key role for budding yeast Senataxin in coordinating replication with transcription (Alzu et al., 2012. Cell). We show that the Senataxin protein associates with replication forks. Senataxin-deficient cells accumulate aberrant replication intermediates and DNA-RNA hybrids while forks clash head-on with RNA polymerase II (RNAPII) transcription units. These replication defects correlate with accumulation of DNA damage signals and genome instability in Senataxin mutants. Altogether our data suggest that Senataxin is recruited at replication forks and, by removing DNA-RNA hybrids that accumulate in transcription-replication collisions, prevents fork instability and DNA damage across RNAPII transcribed units. We also show that Senataxin-deficient cells are resistant to drugs that interfere with microtubule assembly, suggesting that senataxin-dysfunctions affect multiple aspects of cellular metabolism. Together our data provide a new framework for understanding the pathological molecular mechanisms caused by Senataxin deficiencies.