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Cell. 2012 Nov 9;151(4):835-846. doi: 10.1016/j.cell.2012.09.041.

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

Author information

1
The FIRC Institute of Molecular Oncology (IFOM) Foundation, Via Adamello 16, 20139 Milan, Italy.
2
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.
3
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.
4
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.

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.

PMID:
23141540
PMCID:
PMC3494831
DOI:
10.1016/j.cell.2012.09.041
[Indexed for MEDLINE]
Free PMC Article

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