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Inactivation of the SR protein splicing factor ASF/ SF2 results in genomic instability.
SR proteins constitute a family of pre-mRNA splicing factors now thought to play several roles in mRNA metabolism in metazoan cells. Here we provide evidence that a prototypical SR protein, ASF/ SF2, is unexpectedly required for maintenance of genomic stability. We first show that in vivo depletion of ASF/ SF2 results in a hypermutation phenotype likely due to DNA rearrangements, reflected in the rapid appearance of DNA double-strand breaks and high-molecular-weight DNA fragments. Analysis of DNA from ASF/ SF2-depleted cells revealed that the nontemplate strand of a transcribed gene was single stranded due to formation of an RNA:DNA hybrid, R loop structure. Stable overexpression of RNase H suppressed the DNA-fragmentation and hypermutation phenotypes. Indicative of a direct role, ASF/ SF2 prevented R loop formation in a reconstituted in vitro transcription reaction. Our results support a model by which recruitment of ASF/ SF2 to nascent transcripts by RNA polymerase II prevents formation of mutagenic R loop structures.[1]References
- Inactivation of the SR protein splicing factor ASF/SF2 results in genomic instability. Li, X., Manley, J.L. Cell (2005)
