CDK12 regulates DNA repair genes by suppressing intronic polyadenylation

Dubbury, Sara; Boutz, Paul L.; Sharp, Phillip A.

doi:10.1038/s41586-018-0758-y

Cited by 216 publications

(264 citation statements)

References 54 publications

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“…Notably, in the majority of cases these upstream PAS were not found in annotated 3 0 UTRs but in other exons or introns. Recently, it was reported that CDK12 suppresses intronic polyadenylation sites [63]. While our data show up-regulation of intronic PAS, considering the much larger number of potential intronic PAS compared to exonic/UTR PAS, no particular enrichment of intronic PAS was observed among upstream up-regulated PAS.…”

Section: See Materials and Methods)contrasting

confidence: 71%

CDK12 controls G1/S progression by regulating RNAPII processivity at core DNA replication genes

et al. 2019

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CDK12 is a kinase associated with elongating RNA polymerase II (RNAPII) and is frequently mutated in cancer. CDK12 depletion reduces the expression of homologous recombination (HR) DNA repair genes, but comprehensive insight into its target genes and cellular processes is lacking. We use a chemical genetic approach to inhibit analog‐sensitive CDK12, and find that CDK12 kinase activity is required for transcription of core DNA replication genes and thus for G1/S progression. RNA‐seq and ChIP‐seq reveal that CDK12 inhibition triggers an RNAPII processivity defect characterized by a loss of mapped reads from 3′ends of predominantly long, poly(A)‐signal‐rich genes. CDK12 inhibition does not globally reduce levels of RNAPII‐Ser2 phosphorylation. However, individual CDK12‐dependent genes show a shift of P‐Ser2 peaks into the gene body approximately to the positions where RNAPII occupancy and transcription were lost. Thus, CDK12 catalytic activity represents a novel link between regulation of transcription and cell cycle progression. We propose that DNA replication and HR DNA repair defects as a consequence of CDK12 inactivation underlie the genome instability phenotype observed in many cancers.

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Section: See Materials and Methods)contrasting

confidence: 71%

CDK12 controls G1/S progression by regulating RNAPII processivity at core DNA replication genes

et al. 2019

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“…Notably, in contrast to the increase in distinctly positioned intronic polyadenylation events observed upon Cdk12 depletion 28 , we were unable to detect cleavage and polyadenylation at specific sites within gene bodies. We developed an algorithm to quantify sequencing reads with non-genomically encoded polyA tails that map to the distal polyA sites of genes.…”

Section: Resultscontrasting

confidence: 93%

“…Notably, changes in the distribution of the Ser2p signal upon CDK13 mel expression differed distinctly from those observed upon loss of a close paralog, CDK12. In cells lacking CDK12, Ser2p was strongly decreased across the gene body despite an increase in total RNAPII 28 . These data also suggest that CDK13 mel promotes oncogenesis via a mechanism that is distinct from CDK12.…”

Section: Resultsmentioning

confidence: 98%

“…Widespread intronic polyadenylation events were reported to disrupt tumor suppressor genes in leukemia by generating truncated mRNAs and proteins, however the truncation mechanism was not defined 38 . Loss of function mutations in CDK12 in metastatic castration-resistant prostate cancer and serous ovarian carcinomas were reported to cause increased production of truncated RNAs in DNA repair genes 28, 39 . The tumor suppressor function of CDK13 appears to uniquely function to target truncated messages for degradation via PAXT-dependent surveillance, representing an additional mechanism by which the oncogenic activity of prematurely terminated RNAs is countered in normal cells.…”

Section: Discussionmentioning

confidence: 99%

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CDK13 Mutations Drive Melanoma via Accumulation of Prematurely Terminated Transcripts

et al. 2019

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23As CDK13 mel acts via a dominant negative mechanism and no CDK13 mel mutations are 126 observed in the Cyclin binding domain, we hypothesized that Cyclin binding is required for 127 CDK13 mel dominant negative activity. To test whether the canonical CDK13 Cyclin, 128 CCNK 18,22,23 , or the related CCNT1 are required for CDK13 mel dominant negative 129 melanomagenesis in vivo, we co-injected vectors that express melanocyte-specific CDK13 mel and 130 melanocyte-specific CRISPR of ccnK or ccnT1 in the mitfa -/-; BRAF; p53 -/zebrafish melanoma 131 model. ccnK melanocyte-specific CRISPR expedited melanoma in the presence of CDK13 W878L , 132 but not alone ( Figure S1L-M). ccnT1 melanocyte-specific CRISPR suppressed CDK13 W878L and 133 CDK13 R860Q oncogenesis but had no effect by itself ( Figure 1K-L, S1O). PCR across the 134 CRISPR cut site confirmed indels directed by the ccnT1, ccnK, and control gRNAs (Figure 135 S1N). These data indicate that CDK13 mel oncogenesis requires CCNT1 for its dominant negative 136 oncogenic activity. 137 Mutant CDK13 binds chromatin in a dominant negative manner. 138As CDK13 is localized in the nucleus 24 and CDK13 WT can phosphorylate the RNAPII 139

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“…Initiation of PROMPT and pre-mRNA transcription occurs at the edge of the nucleosome depleted region (NDR) in a bidirectional manner (Ntini et al, 2013;Andersson et al, 2014aAndersson et al, , 2014bDubbury et al, 2018) . Unlike pre-mRNAs, PROMPTs are rapidly degraded by the nuclear exosome (Preker et al, 2008) , a central player in RNA degradation.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Arabidopsis thaliana promoter bidirectionality and antisense RNAs by depletion of nuclear RNA decay enzymes

Thieffry

Bornholdt

Ivanov

et al. 2019

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In animals, transcription by RNA polymerase II initiates bidirectionally from gene promoters to produce pre-mRNAs on the forward strand and promoter upstream transcripts (PROMPTs) on the reverse strand. PROMPTs are rapidly degraded by the nuclear exosome. Similarly, active enhancer regions in animals initiate transcription of exosome-sensitive enhancer RNAs (eRNAs). Previous studies based on nascent RNA approaches concluded that Arabidopsis thaliana does not produce PROMPTs . Here, we used steady-state RNA sequencing methods in mutants defective in nuclear RNA decay, including by the exosome, to reassess the existence of PROMPTs and eRNAs in A. thaliana . While PROMPTs are overall rare in A. thaliana , about 100 clear cases of exosome-sensitive PROMPTs and 113 loci producing eRNA-like transcripts were identified. In addition, we found~200 transcription start sites within 3'-UTR-encoding regions that produce unspliced exosome-sensitive antisense RNAs covering much of the cognate pre-mRNA. A typical representative of this class of RNAs is the previously characterized non-coding RNA controlling the expression of the key seed dormancy regulator, DELAY OF GERMINATION1 . Exosome-sensitive antisense RNAs are overrepresented in transcription factor genes, suggesting a potential for widespread control of gene expression.Lastly, we assess the use of alternative promoters in A. thaliana and compare the accuracy of existing TSS annotations.

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CDK12 regulates DNA repair genes by suppressing intronic polyadenylation

Cited by 216 publications

References 54 publications

CDK12 controls G1/S progression by regulating RNAPII processivity at core DNA replication genes

CDK12 controls G1/S progression by regulating RNAPII processivity at core DNA replication genes

CDK13 Mutations Drive Melanoma via Accumulation of Prematurely Terminated Transcripts

Characterization of Arabidopsis thaliana promoter bidirectionality and antisense RNAs by depletion of nuclear RNA decay enzymes

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