Senataxin associates with replication forks to protect fork integrity across RNA-polymerase-II-transcribed genes

Amaya Alzu, Rodrigo Bermejo, Martina Begnis, Chiara Lucca, Daniele Piccini, Walter Carotenuto, Marco Saponaro, Alessandra Brambati, Andrea Cocito, Marco Foiani, Giordano Liberi

Research output: Contribution to journalArticlepeer-review

136 Citations (Scopus)


Transcription hinders replication fork progression and stability. The ATR checkpoint and specialized DNA helicases assist DNA synthesis across transcription units to protect genome integrity. Combining genomic and genetic approaches together with the analysis of replication intermediates, we searched for factors coordinating replication with transcription. We show that the Sen1/Senataxin DNA/RNA helicase associates with forks, promoting their progression across RNA polymerase II (RNAPII)-transcribed genes. sen1 mutants accumulate aberrant DNA structures and DNA-RNA hybrids while forks clash head-on with RNAPII transcription units. These replication defects correlate with hyperrecombination and checkpoint activation in sen1 mutants. The Sen1 function at the forks is separable from its role in RNA processing. Our data, besides unmasking a key role for Senataxin in coordinating replication with transcription, provide a framework for understanding the pathological mechanisms caused by Senataxin deficiencies and leading to the severe neurodegenerative diseases ataxia with oculomotor apraxia type 2 and amyotrophic lateral sclerosis 4.

Original languageEnglish
Pages (from-to)835-46
Number of pages12
Issue number4
Publication statusPublished - 9 Nov 2012


  • DNA Helicases
  • DNA Replication
  • Humans
  • Neurodegenerative Diseases
  • RNA Helicases
  • RNA Polymerase II
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Transcription, Genetic


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