The RNA Splicing Response to DNA Damage

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.

DDX54 regulates transcriptome dynamics during DNA damage response

“…Recognition of the importance of RBPs for the DDR has increased in recent years (Lenzken et al 2013;Dutertre et al 2014;Naro et al 2015;Shkreta and Chabot 2015;Kai 2016). Using differential quantification of the poly(A) + RNA-protein interactome, we identified more than 260 RBPs that displayed increased binding activity to polyadenylated transcripts upon induction of DSBs in cultured human breast cancer cells.…”

“…On the cellular level, DDR impacts multiple layers of cell fate decisions from activation of specific DNA repair mechanisms, cell cycle progression/arrest, to apoptotic or senescent phenotypes (Zhou and Elledge 2000). Importantly, a significant fraction of these decisions are mediated by a transcriptional response, which is largely under the control of TP53, a transcription factor that regulates expression of cell cycle regulators such as cyclin-dependent inhibitor protein 1A (CDKN1A/p21), apoptotic proteins (e.g., BAX, BBC3/PUMA), and DNA repair components (Riley et al 2008;Shkreta and Chabot 2015).…”

“…The major trans-acting regulators of the RNA lifecycle are RNA-binding proteins (RBPs) whose emerging role has been recognized in many aspects of the DDR (for reviews, see Reinhardt et al 2011;Lenzken et al 2013;Dutertre et al 2014;Naro et al 2015;Shkreta and Chabot 2015;Kai 2016). Several recent large-scale proteomic studies have reported that RNA processing and translation factors are post-translationally modified by DDR signaling (Matsuoka et al 2007;Bennetzen et al 2010;Bensimon et al 2010;Beli et al 2012;Jungmichel et al 2013), and many RBPs are essential for the DDR (Paulsen et al 2009;Adamson et al 2012;Boucas et al 2015).…”

“…Several recent large-scale proteomic studies have reported that RNA processing and translation factors are post-translationally modified by DDR signaling (Matsuoka et al 2007;Bennetzen et al 2010;Bensimon et al 2010;Beli et al 2012;Jungmichel et al 2013), and many RBPs are essential for the DDR (Paulsen et al 2009;Adamson et al 2012;Boucas et al 2015). Specifically, some RNA processing factors (EWSR1, THRAP3, RBMX, NONO, HRNPC, YBX1, RBM14) can be either recruited to DSBs, relocalized upon DNA damage and/or directly contribute to DNA repair (Paronetto et al 2011;Rajesh et al 2011;Adamson et al 2012;Beli et al 2012;Krietsch et al 2012;Polo et al 2012;Anantha et al 2013;Chang et al 2014;Shkreta and Chabot 2015;Simon et al 2017), whereas others such as SRSF10 impact alternative splicing of transcripts coding for proteins involved in DNA repair, cell cycle control, and apoptosis (Shkreta et al 2016). Notably, somatic mutations very often occur in genes encoding RNA splicing factors, thus leading to widespread misregulated splicing events in many tumor types (Sebestyén et al 2016).…”

SIRT1 Involved in the Regulation of Alternative Splicing Affects the DNA Damage Response in Neural Stem Cells

“…DNA damage can alter the gene expression, subcellular localization, and protein modification of splicing factors, which ultimately affect the production of components that control cell fate through splicing [9][10][11][12][13][14]. Previous work has indicated that AS of genes involved in DNA damage response (DDR)-related processes, such as DNA repair, cell cycle control, and apoptosis, are extensively modulated by DNA damage [15]. On the other hand, deficiencies in some splicing factors can also induce DNA damage [16,17], which suggests a close cross-regulation between AS and DNA damage.…”