title: Senataxin associates with replication forks to protect fork integrity across RNA-polymerase-II-transcribed genes.
abstract: 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.
authors.affiliation: The FIRC Institute of Molecular Oncology (IFOM) Foundation, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Amaya
authors.initials: A
authors.lastname: Alzu
authors.affiliation: The FIRC Institute of Molecular Oncology (IFOM) Foundation, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Bermejo
authors.affiliation: The FIRC Institute of Molecular Oncology (IFOM) Foundation, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Begnis
authors.affiliation: The FIRC Institute of Molecular Oncology (IFOM) Foundation, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Lucca
authors.affiliation: The FIRC Institute of Molecular Oncology (IFOM) Foundation, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Piccini
authors.affiliation: The FIRC Institute of Molecular Oncology (IFOM) Foundation, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Walter
authors.initials: W
authors.lastname: Carotenuto
authors.affiliation: The FIRC Institute of Molecular Oncology (IFOM) Foundation, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Saponaro
authors.affiliation: The FIRC Institute of Molecular Oncology (IFOM) Foundation, Via Adamello 16, 20139 Milan, Italy; Istituto di Genetica Molecolare del Consiglio Nazionale delle Ricerche (IGM-CNR), Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Brambati
authors.affiliation: The FIRC Institute of Molecular Oncology (IFOM) Foundation, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cocito
authors.affiliation: The FIRC Institute of Molecular Oncology (IFOM) Foundation, Via Adamello 16, 20139 Milan, Italy; DSBB-Università degli Studi di Milano, Via Celoria 26, 20139 Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Foiani
authors.affiliation: The FIRC Institute of Molecular Oncology (IFOM) Foundation, Via Adamello 16, 20139 Milan, Italy; Istituto di Genetica Molecolare del Consiglio Nazionale delle Ricerche (IGM-CNR), Via Abbiategrasso 207, 27100 Pavia, Italy. Electronic address: giordano.liberi@igm.cnr.it.
authors.forename: Giordano
authors.initials: G
authors.lastname: Liberi
mesh_terms: D004265:DNA Helicases / Q000378:metabolism*; D004261:DNA Replication; D006801:Humans; D019636:Neurodegenerative Diseases / Q000378:metabolism; D020365:RNA Helicases / Q000378:metabolism*; D012319:RNA Polymerase II / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D029701:Saccharomyces cerevisiae Proteins; D012319:RNA Polymerase II; C542347:SEN1 protein, S cerevisiae; D004265:DNA Helicases; D020365:RNA Helicases