Senataxin, Defective in the Neurodegenerative Disorder Ataxia with Oculomotor Apraxia 2, Lies at the Interface of Transcription and the DNA Damage Response

Abstract

The neurodegenerative disorder ataxia with oculomotor apraxia 2 (AOA-2) is caused by defects in senataxin, a putative RNA/ DNA helicase thought to be involved in the termination of transcription at RNA polymerase pause sites. RNA/DNA hybrids (R loops) that arise during transcription pausing lead to genome instability unless they are resolved efficiently. We found that senataxin forms distinct nuclear foci in S/G 2 -phase human cells and that the number of these foci increases in response to impaired DNA replication or DNA damage. Senataxin colocalizes with 53BP1, a key DNA damage response protein, and with other factors involved in DNA repair. Inhibition of transcription using ␣-amanitin, or the dissolution of R loops by transient expression of RNase H1, leads to the loss of senataxin foci. These results indicate that senataxin localizes to sites of collision between components of the replisome and the transcription apparatus and that it is targeted to R loops, where it plays an important role at the interface of transcription and the DNA damage response.

Systematic screening reveals a role for BRCA1 in the response to transcription-associated DNA damage

“…Imputed functions of TONSL and known functions of the TONSL-binding FACT complex and of SETX, TCEANC, and TCEA2-all proteins engaged in transcription and/or RNA processing and all proteins that genetically interact with BRCA1-represent new processes through which BRCA1 participates in the prevention and/or repair of DNA damage. That BRCA1 is engaged in transcriptionassociated damage control is supported as a concept by these results and by BRCA1-and BARD1-linked phenomena observed by others (Scully et al 1997;Manley 1999, 2001;Le Page et al 2000;Kleiman et al 2005;Becherel et al 2013;Yuce and West 2013;Bhatia et al 2014). Moreover, data reported here now strongly suggest that BRCA1 responds to DNA damage at sites of stalled or defective transcription to either aid in transcription restart and/or resolve certain damaged structures at these sites.…”

A SUMO-dependent interaction between Senataxin and the exosome, disrupted in the neurodegenerative disease AOA2, targets the exosome to sites of transcription-induced DNA damage

“…One possibility is suggested by two recent studies in humans and yeast revealing that SETX/Sen1 functions to resolve R loops when transcription and replication machineries collide (Alzu et al 2012;Yuce and West 2013), which can otherwise result in DNA damage and genomic instability (Gan et al 2011;Helmrich et al 2011). Notably, considerable evidence also suggests that SUMO plays important roles in the DNA damage response (Jackson and Durocher 2013).…”

“…Indeed, Sen1 is located at replication forks and displaces R loops to allow fork progression across RNAP II transcription units (Alzu et al 2012). Likewise, a recent study suggests that SETX also resolves R-loop structures formed at sites of collision between the transcription and replication machineries, in conjunction with DNA repair factors (Yuce and West 2013). Consistent with this, disruption of SETX in mice revealed an accumulation of R loops and double-strand breaks (DSBs) in germ cells (Becherel et al 2013).…”

Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1

“…Mutations affecting the helicase domain of two SF1 members, IGHMBP2 and SETX, cause motor neuron disease (39,40), indicating a selective vulnerability of motor neurons to functional deficiencies in certain RNA helicases. IGHMBP2 participates in mRNA decay, transcription, and translation (41,42), whereas SETX functions in transcription and the DNA damage response (43). MOV10 localizes to P-bodies, cytoplasmic sites of RNA processing (44), and directly promotes NMD by unwinding pre-mRNA transcripts and removing bound proteins (45).…”