Abstract
The number of factors known to participate in the DNA damage response (DDR) has expanded considerably in recent years to include splicing and alternative splicing factors. While the binding of splicing proteins and ribonucleoprotein complexes to nascent transcripts prevents genomic instability by deterring the formation of RNA/DNA duplexes, splicing factors are also recruited to, or removed from, sites of DNA damage. The first steps of the DDR promote the post-translational modification of splicing factors to affect their localization and activity, while more downstream DDR events alter their expression. Although descriptions of molecular mechanisms remain limited, an emerging trend is that DNA damage disrupts the coupling of constitutive and alternative splicing with the transcription of genes involved in DNA repair, cell-cycle control and apoptosis. A better understanding of how changes in splice site selection are integrated into the DDR may provide new avenues to combat cancer and delay aging.
Highlights
Genomes are continuously bruised by products of normal cell metabolism and by errors in DNA replication
SRSF1 stimulates the sumoylation of Sam68 [61], it is not known whether DNA damage affects the sumoylation of Sam68, and whether the splicing functions of Sam68 and hnRNP K are affected by sumoylation
Recent efforts have helped establish the multiple ways through which DNA damage alters the activity of splicing factors and modulates constitutive and alternative splicing
Summary
Genomes are continuously bruised by products of normal cell metabolism and by errors in DNA replication. While DNA damage impacts nearly every aspect of gene expression, including. Biomolecules 2015, 5 transcription and translation, more attention has recently been devoted to studying how DNA damage affects post-transcriptional events, with several excellent reviews published on this topic [1,2,3,4,5]. We review the interconnections that exist between DNA damage and pre-mRNA splicing. We present examples showing that DNA damage often disrupts splicing by interfering with its coupling to transcription. We summarize a growing body of data that document the impact of DNA damage on the splicing and alternative splicing of genes intimately associated with the DDR and with cell fate
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