Control of the RNA polymerase II phosphorylation state in promoter regions by CTD interaction domain-containing proteins RPRD1A and RPRD1B

Ni, Zuyao; Olsen, Jonathan B.; Guo, Xinghua; Zhong, Guoqing; Ruan, Eric Dongliang; Marcon, Edyta; Young, P.; Guo, Hongbo; Li, Joyce; Moffat, Jason; Emili, Andrew; Greenblatt, Jack

doi:10.4161/trns.2.5.17803

Cited by 58 publications

(97 citation statements)

References 44 publications

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“…The phosphorylated status of CTD at Ser-2, Ser-5, as well as Ser-7 was present during the initiation, elongation, and termination of gene transcription (8 -10). Recently, Ni et al (11) reported that CREPT/RPRD1B, and also p15RS/RPRD1A and RPRD2, were co-purified with RNAP II. It appeared that CREPT/ RPRD1B and p15RS/RPRD1A preferentially bound to the phosphorylated CTD of RNAP II, leading to decreased Ser-5 and Ser-7 phosphorylation of RNAP II at target gene promoters (11).…”

Section: C20orf77mentioning

confidence: 99%

CREPT/RPRD1B, a Recently Identified Novel Protein Highly Expressed in Tumors, Enhances the β-Catenin·TCF4 Transcriptional Activity in Response to Wnt Signaling

Zhang

Liu

Duan

et al. 2014

Journal of Biological Chemistry

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Background: CREPT/RPRD1B promotes tumor growth through up-regulating CYCLIN D1 expression. Results: CREPT interacts with ␤-catenin in response to Wnt signaling and enhances the occupancy of ␤-catenin to promoters of Wnt-targeted genes, resulting in an up-regulation of expression. Conclusion: CREPT functions as a co-activator for ␤-catenin⅐TCF4. Significance: CREPT-regulated Wnt signaling implies an oncogenic role in promoting cell proliferation and invasion.

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Section: C20orf77mentioning

confidence: 99%

CREPT/RPRD1B, a Recently Identified Novel Protein Highly Expressed in Tumors, Enhances the β-Catenin·TCF4 Transcriptional Activity in Response to Wnt Signaling

Zhang

Liu

Duan

et al. 2014

Journal of Biological Chemistry

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“…CSTF3 has direct functional connection with CDK12 being involved in the 3 0 end formation of pre-mRNA, a process coupled with CDK12-dependent Ser2 CTD phosphorylation (38). The top downregulated gene in CDK12-mutated tumors, validated in all cohorts, is RPRD1A (Regulation of Nuclear Pre-mRNA Domain Containing 1A), which interacts with phosphorylated CTD of the RNA pol II and participates in dephosphorylation of the CTD (39). Consistent downregulation of CSTF3 and RPRD1A may evidence a compensatory mechanism developed by tumors upon CDK12 inactivation, which would explain the different gene sets obtained in tumors and cellular models.…”

Section: à15mentioning

confidence: 99%

Ovarian Cancers Harboring Inactivating Mutations in CDK12 Display a Distinct Genomic Instability Pattern Characterized by Large Tandem Duplications

et al. 2016

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CDK12 is a recurrently mutated gene in serous ovarian carcinoma, whose downregulation is associated with impaired expression of DNA damage repair genes and subsequent hypersensitivity to DNA-damaging agents and PARP1/2 inhibitors. In this study, we investigated the genomic landscape associated with CDK12 inactivation in patients with serous ovarian carcinoma. We show that CDK12 loss was consistently associated with a particular genomic instability pattern characterized by hundreds of tandem duplications of up to 10 megabases (Mb) in size. Tandem duplications were characterized by a bimodal ($0.3 and $3 Mb) size distribution and overlapping microhomology at the breakpoints.This genomic instability, denoted as the CDK12 TD-plus phenotype, is remarkably distinct from other alteration patterns described in breast and ovarian cancers. The CDK12 TD-plus phenotype was associated with a greater than 10% gain in genomic content and occurred at a 3% to 4% rate in The Cancer Genome Atlas-derived and in-house cohorts of patients with serous ovarian carcinoma. Moreover, CDK12-inactivating mutations together with the TD-plus phenotype were also observed in prostate cancers. Our finding provides new insight toward deciphering the function of CDK12 in genome maintenance and oncogenesis. Cancer Res; 76(7); 1882-91. Ó2016 AACR.

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“…these effects of the drug indeed affected the engagement of RNAPII in transcription. Ser-5-hyperphosphorylated RNAPII is known to be mainly located near gene promoter regions (13). Therefore, we first conducted ChIP assays by using an antibody against the N-terminal domain of RNAPII in the PC-3 cells treated with triptolide to see whether the chromatin-bound RNAPII at the promoter regions of transcribed genes reduces.…”

Section: Triptolide-induced Block Of Rnapii At Promoters Precedes Chrmentioning

confidence: 99%

“…11) and other residues (12), which depends on the type of transcriptional stress or stalling. The CTD consists of multiple repeats of the consensus sequence Y 1 S 2 P 3 T 4 S 5 P 6 S 7 , plays a fundamental role in regulating the RNAPII-mediated transcription, and the stability of Rpb1 (8,13,14). Phosphorylation at Ser-5 and Ser-2 of the CTD regulates transcription initiation and elongation, respectively, at specific steps (14,15).…”

Section: Introductionmentioning

confidence: 99%

Natural Product Triptolide Mediates Cancer Cell Death by Triggering CDK7-Dependent Degradation of RNA Polymerase II

et al. 2012

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Triptolide is a bioactive ingredient in traditional Chinese medicine that exhibits diverse biologic properties, including anticancer properties. Among its many putative targets, this compound has been reported to bind to XPB, the largest subunit of general transcription factor TFIIH, and to cause degradation of the largest subunit Rpb1 of RNA polymerase II (RNAPII). In this study, we clarify multiple important questions concerning the significance and basis for triptolide action at this core target. Triptolide decreased Rpb1 levels in cancer cells in a manner that was correlated tightly with its cytotoxic activity. Compound exposure blocked RNAPII at promoters and decreased chromatin-bound RNAPII, both upstream and within all genes that were examined, also leading to Ser-5 hyperphosphorylation and increased ubiqutination within the Rbp1 carboxy-terminal domain. Notably, cotreatment with inhibitors of the proteasome or the cyclin-dependent kinase CDK7 inhibitors abolished the ability of triptolide to ablate Rpb1. Together, our results show that triptolide triggers a CDK7-mediated degradation of RNAPII that may offer an explanation to many of its therapeutic properties, including its robust and promising anticancer properties. Cancer Res; 72(20); 5363-73. Ó2012 AACR.

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Control of the RNA polymerase II phosphorylation state in promoter regions by CTD interaction domain-containing proteins RPRD1A and RPRD1B

Cited by 58 publications

References 44 publications

CREPT/RPRD1B, a Recently Identified Novel Protein Highly Expressed in Tumors, Enhances the β-Catenin·TCF4 Transcriptional Activity in Response to Wnt Signaling

CREPT/RPRD1B, a Recently Identified Novel Protein Highly Expressed in Tumors, Enhances the β-Catenin·TCF4 Transcriptional Activity in Response to Wnt Signaling

Ovarian Cancers Harboring Inactivating Mutations in CDK12 Display a Distinct Genomic Instability Pattern Characterized by Large Tandem Duplications

Natural Product Triptolide Mediates Cancer Cell Death by Triggering CDK7-Dependent Degradation of RNA Polymerase II

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