Reciprocal regulation between alternative splicing and the DNA damage response

Abstract

Splicing, the process that catalyzes intron removal and flanking exon ligation, can occur in different ways (alternative splicing) in immature RNAs transcribed from a single gene. In order to adapt to a particular context, cells modulate not only the quantity but also the quality (alternative isoforms) of their transcriptome. Since 95% of the human coding genome is subjected to alternative splicing regulation, it is expected that many cellular pathways are modulated by alternative splicing, as is the case for the DNA damage response. Moreover, recent evidence demonstrates that upon a genotoxic insult, classical DNA damage response kinases such as ATM, ATR and DNA-PK orchestrate the gene expression response therefore modulating alternative splicing which, in a reciprocal way, shapes the response to a damaging agent.

Figure 1. Roles recently reported for the kinases ATR, ATM and DNA-PK are depicted. UV-induced DNA lesions activate ATR and ATM, the latter being activated in particular by stalling of transcribing RNAPII. Double strand breaks (DSB) activate ATM and DNA-PK. These three central DDR kinases modulate gene expression globally, both by regulating gene expression levels and by modifying AS patterns. This modulation, in turn, tunes the DDR by modulating cell-cycle regulation, DNA repair and cell death.