RNA Splicing: A New Player in the DNA Damage Response

Lenzken, Silvia C.; Loffreda, Alessia; Barabino, Silvia M.L.

doi:10.1155/2013/153634

Cited by 42 publications

(37 citation statements)

References 131 publications

(144 reference statements)

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

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confidence: 99%

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DDX54 regulates transcriptome dynamics during DNA damage response

et al. 2017

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The cellular response to genotoxic stress is mediated by a well-characterized network of DNA surveillance pathways. The contribution of post-transcriptional gene regulatory networks to the DNA damage response (DDR) has not been extensively studied. Here, we systematically identified RNA-binding proteins differentially interacting with polyadenylated transcripts upon exposure of human breast carcinoma cells to ionizing radiation (IR). Interestingly, more than 260 proteins, including many nucleolar proteins, showed increased binding to poly(A) + RNA in IR-exposed cells. The functional analysis of DDX54, a candidate genotoxic stress responsive RNA helicase, revealed that this protein is an immediate-to-early DDR regulator required for the splicing efficacy of its target IR-induced pre-mRNAs. Upon IR exposure, DDX54 acts by increased interaction with a well-defined class of pre-mRNAs that harbor introns with weak acceptor splice sites, as well as by proteinprotein contacts within components of U2 snRNP and spliceosomal B complex, resulting in lower intron retention and higher processing rates of its target transcripts. Because DDX54 promotes survival after exposure to IR, its expression and/or mutation rate may impact DDR-related pathologies. Our work indicates the relevance of many uncharacterized RBPs potentially involved in the DDR.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

DDX54 regulates transcriptome dynamics during DNA damage response

et al. 2017

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“…For instance, some mutant p53 proteins can drive breast cancer [88], and the alternative splicing of cyclin D1 mRNA leads to distinct protein forms with opposite activities on cell cycling (G1-S progression inhibition, S-G2/M progression acceleration and apoptosis enhancement or delay) [92,93,94]. In addition, alternative RNA processing has emerged as a new pathway in genome maintenance that affects the expression of protein forms involved in both RNA splicing and genome surveillance [95]. The functions of HLTF truncated forms might act as oncogenic proteins and/or interfere with the normal activities of wt HLTF as dominant negative oncomorphic forms of a tumor suppressor.…”

Section: Discussionmentioning

confidence: 99%

The helicase-like transcription factor (HLTF) in cancer: loss of function or oncomorphic conversion of a tumor suppressor?

Dhont

Mascaux

Belayew

2015

Cell. Mol. Life Sci.

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The Helicase-like Transcription Factor (HLTF) belongs to the SWI/SNF family of proteins involved in chromatin remodeling. In addition to its role in gene transcription, HLTF has been implicated in DNA repair, which suggests that this protein acts as a tumor suppressor. Accumulating evidence indicates that HLTF expression is altered in various cancers via two mechanisms: gene silencing through promoter hypermethylation or alternative mRNA splicing, which leads to the expression of truncated proteins that lack DNA repair domains. In either case, the alteration of HLTF expression in cancer has a poor prognosis. In this review, we gathered published clinical and molecular data on HLTF. Our purposes are (a) to address whether HLTF alterations could be considered as cancer drivers or passengers and (b) to determine whether its different functions (transcription or DNA repair) could be diverted in clonal selection during cancer progression.

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“…Later DDR stages, involve changes in gene expression. Emerging evidence supports that DNA damage influences not only expression levels of its target genes, by altering transcription rates and mRNA half-life, but also exon selection and ultimately their coding potential 6 .…”

Section: Introductionmentioning

confidence: 99%

The core spliceosome as target and effector of non-canonical ATM signalling

Tresini

Warmerdam

Kolovos

et al. 2015

Nature

229

237

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In response to DNA damage tissue homoeostasis is ensured by protein networks promoting DNA repair, cell cycle arrest or apoptosis. DNA damage response signaling pathways coordinate these processes, partly by propagating gene expression-modulating signals. DNA damage influences not only abundance of mRNAs, but also their coding information through alternative splicing. Here we show that transcription-blocking DNA lesions promote chromatin displacement of late-stage spliceosomes and initiate a positive feedback loop centered on the signaling kinase ATM. We propose that initial spliceosome displacement and subsequent R-loop formation is triggered by pausing of RNA polymerase at DNA lesions. In turn, R-loops activate ATM which signals to further impede spliceosome organization and augment UV-triggered alternative splicing at genome-wide level. Our findings define the R-loop-dependent ATM activation by transcription-blocking lesions as an important event in the DNA damage response of non-replicating cells and highlight a key role for spliceosome displacement in this process.

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RNA Splicing: A New Player in the DNA Damage Response

Cited by 42 publications

References 131 publications

DDX54 regulates transcriptome dynamics during DNA damage response

DDX54 regulates transcriptome dynamics during DNA damage response

The helicase-like transcription factor (HLTF) in cancer: loss of function or oncomorphic conversion of a tumor suppressor?

The core spliceosome as target and effector of non-canonical ATM signalling

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