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

Tresini, Maria; Warmerdam, Daniël O.; Kolovos, Petros; Snijder, Loes; Vrouwe, Mischa G.; Demmers, Jeroen; IJcken, Wilfred F. J. van; Grosveld, Frank; Medema, René H.; Hoeijmakers, Jan H.J.; Mullenders, Leon H.F.; Vermeulen, Wim; Marteijn, Jürgen A.

doi:10.1038/nature14512

Cited by 229 publications

(276 citation statements)

References 45 publications

(70 reference statements)

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“…Another recent report shows that R-loop-mediated ATM activation regulates the expression of target genes and accelerates alternative pre-mRNA splicing in a genome-wide manner to produce new gene products following irradiation with ultraviolet C (UVC) (Tresini et al, 2015).…”

Section: Box 2 Atr and Atm As Targets For Cancer Therapymentioning

confidence: 99%

ATM and ATR signaling at a glance

Awasthi

Foiani

Kumar

2015

Journal of Cell Science

235

228

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There was an error published in J. Cell Sci. 128, 4255-4262.An incorrect citation and reference was given for the last sentence in Box 2. The correct citation and reference are: A recent review provides a detailed update on ATM and ATR inhibitors, and their potential as drug targets (Weber and Ryan, 2015).Weber, A.M. and Ryan, A.J. (2015). ATM and ATR as therapeutic targets in cancer. Pharmacol Ther. 149, 124-138.The authors apologise to the readers for any confusion that this error might have caused. Although the role of both ATM and ATR in DNA repair, cell cycle regulation and apoptosis have been well studied, both still remain in the focus of current research activities owing to their role in cancer. Recent advances in the field suggest that these proteins have an additional function in maintaining cellular homeostasis under both stressed and non-stressed conditions. In this Cell Science at a Glance article and the accompanying poster, we present an overview of recent advances in ATR and ATM research with emphasis on that into the modes of ATM and ATR activation, the different signaling pathways they participate in -including those that do not involve DNA damage -and highlight their relevance in cancer. 1285

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Section: Box 2 Atr and Atm As Targets For Cancer Therapymentioning

confidence: 99%

ATM and ATR signaling at a glance

Awasthi

Foiani

Kumar

2015

Journal of Cell Science

235

228

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“…DNA damage often results from excessive R-loop formation (Sollier and Cimprich, 2015), which has been reported in Srsf1 - and Srsf2 -ablated cells (Li and Manley, 2005; Xiao et al, 2007) and linked to certain core splicing factors (Tresini et al, 2015). However, it has been demonstrated, in the case of SRSF2 , that the mutation caused a gain of function in binding to CCNG motifs (Kim et al, 2015; Zhang et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

The Augmented R-Loop Is a Unifying Mechanism for Myelodysplastic Syndromes Induced by High-Risk Splicing Factor Mutations

et al. 2018

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SUMMARY Mutations in several general pre-mRNA splicing factors have been linked to myelodysplastic syndromes (MDSs) and solid tumors. These mutations have generally been assumed to cause disease by the resultant splicing defects, but different mutations appear to induce distinct splicing defects, raising the possibility that an alternative common mechanism is involved. Here we report a chain of events triggered by multiple splicing factor mutations, especially high-risk alleles in SRSF2 and U2AF1, including elevated R-loops, replication stress, and activation of the ataxia telangiectasia and Rad3-related protein (ATR)-Chk1 pathway. We further demonstrate that enhanced R-loops, opposite to the expectation from gained RNA binding with mutant SRSF2, result from impaired transcription pause release because the mutant protein loses its ability to extract the RNA polymerase II (Pol II) C-terminal domain (CTD) kinase—the positive transcription elongation factor complex (P-TEFb)—from the 7SK complex. Enhanced R-loops are linked to compromised proliferation of bone-marrow-derived blood progenitors, which can be partially rescued by RNase H overexpression, suggesting a direct contribution of augmented R-loops to the MDS phenotype.

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“…The tight coordination of splicing with other cellular processes (eg, transcription initiation and elongation, histone modification and DNA methylation, mRNA export and translation, DNA damage response) [101][102][103][104][105][106][107][108][109] suggests that splicing factor mutations may create vulnerabilities in other pathways. Unbiased small molecule and genetic screens may uncover additional potentially druggable targets, some of which could be candidates for drug development.…”

Section: Targeting Signaling Inputs To Splicingmentioning

confidence: 99%

Splicing factor gene mutations in hematologic malignancies

Sáez

Walter

Graubert

2017

Blood

112

108

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Alternative splicing generates a diversity of messenger RNA (mRNA) transcripts from a single mRNA precursor and contributes to the complexity of our proteome. Splicing is perturbed by a variety of mechanisms in cancer. Recurrent mutations in splicing factors have emerged as a hallmark of several hematologic malignancies. Splicing factor mutations tend to occur in the founding clone of myeloid cancers, and these mutations have recently been identified in blood cells from normal, healthy elderly individuals with clonal hematopoiesis who are at increased risk of subsequently developing a hematopoietic malignancy, suggesting that these mutations contribute to disease initiation. Splicing factor mutations change the pattern of splicing in primary patient and mouse hematopoietic cells and alter hematopoietic differentiation and maturation in animal models. Recent developments in this field are reviewed here, with an emphasis on the clinical consequences of splicing factor mutations, mechanistic insights from animal models, and implications for development of novel therapies targeting the precursor mRNA splicing pathway. (Blood. 2017;129(10):1260-1269 IntroductionThe control of messenger RNA (mRNA) processing is a crucial component of gene regulation. The precursor messenger RNA (premRNA) sequence contains exons that flank introns, which are removed during splicing.1 Human genes are remarkably complex, containing an average of 8 exons, with introns composing up to 90% of the pre-mRNA sequence.2,3 Up to 94% of human genes generate multiple mRNA isoforms. [4][5][6] The spliceosome is a multiprotein complex consisting of 5 small nuclear ribonucleoproteins (snRNPs) and more than 150 proteins that recognizes the elements near intron-exon boundaries and the branch site that catalyzes the excision of intronic regions. Additional trans-acting factors including SR proteins bind the cis-regulatory sequences (exonic and intronic silencers and enhancers) to promote or prevent spliceosome assembly. [7][8][9] The complexity of regulatory elements that control proper splicing makes this process not only critical to maintain tissue homeostasis, but also highly susceptible to hereditary and somatic mutations that are involved in disease. This review will discuss the implications of aberrant splicing on human disease, with a focus on the impact of somatic mutations in trans-acting splicing factors in hematologic malignancies. Splicing and diseaseA comprehensive analysis of The Cancer Genome Atlas (TCGA) project RNA sequencing (RNA-seq) data from 16 tumor types and matched normal tissue revealed evidence of global alternative splicing involving a variety of splicing junctions, including cassette exons, retrained introns, and competing 59 and 39 splice sites (SSs). 10 In particular, acute myeloid leukemia (AML) cells showed the largest number of alternative spliced events among tumor types.10 Recent evidence from analysis of paired DNA and RNA-seq data from TCGA has shown that somatic mutations affecting splicing regulatory sequences (sp...

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

Cited by 229 publications

References 45 publications

ATM and ATR signaling at a glance

ATM and ATR signaling at a glance

The Augmented R-Loop Is a Unifying Mechanism for Myelodysplastic Syndromes Induced by High-Risk Splicing Factor Mutations

Splicing factor gene mutations in hematologic malignancies

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