Heterogeneous Nuclear Ribonucleoprotein (HnRNP) K Genome-wide Binding Survey Reveals Its Role in Regulating 3′-End RNA Processing and Transcription Termination at the Early Growth Response 1 (EGR1) Gene through XRN2 Exonuclease*

Mikula, Michał; Bomsztyk, Karol; Goryca, Krzysztof; Chojnowski, Krzysztof; Ostrowski, Jerzy

doi:10.1074/jbc.m113.496679

Cited by 30 publications

(32 citation statements)

References 46 publications

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“…Under these conditions, we detected increased readthrough transcripts of MYC and FRAT2 (Fig. 6F), consistent with previous reports (West et al 2004;Mikula et al 2013). We also saw increased transcription past normal CCNB1 termination signals by conventional PCR-with a forward primer upstream of the PAS and reverse primers at increasing distances downstream-after Xrn2 depletion or CDK inhibition (Supplemental Fig.…”

Section: Cdks and Xrn2 Phosphorylation Promote Transcription Terminationsupporting

confidence: 80%

P-TEFb regulation of transcription termination factor Xrn2 revealed by a chemical genetic screen for Cdk9 substrates

et al. 2016

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The transcription cycle of RNA polymerase II (Pol II) is regulated at discrete transition points by cyclin-dependent kinases (CDKs). Positive transcription elongation factor b (P-TEFb), a complex of Cdk9 and cyclin T1, promotes release of paused Pol II into elongation, but the precise mechanisms and targets of Cdk9 action remain largely unknown. Here, by a chemical genetic strategy, we identified ∼100 putative substrates of human P-TEFb, which were enriched for proteins implicated in transcription and RNA catabolism. Among the RNA processing factors phosphorylated by Cdk9 was the 5 ′ -to-3 ′ "torpedo" exoribonuclease Xrn2, required in transcription termination by Pol II, which we validated as a bona fide P-TEFb substrate in vivo and in vitro. Phosphorylation by Cdk9 or phosphomimetic substitution of its target residue, Thr439, enhanced enzymatic activity of Xrn2 on synthetic substrates in vitro. Conversely, inhibition or depletion of Cdk9 or mutation of Xrn2-Thr439 to a nonphosphorylatable Ala residue caused phenotypes consistent with inefficient termination in human cells: impaired Xrn2 chromatin localization and increased readthrough transcription of endogenous genes. Therefore, in addition to its role in elongation, P-TEFb regulates termination by promoting chromatin recruitment and activation of a cotranscriptional RNA processing enzyme, Xrn2.

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Section: Cdks and Xrn2 Phosphorylation Promote Transcription Terminationsupporting

confidence: 80%

P-TEFb regulation of transcription termination factor Xrn2 revealed by a chemical genetic screen for Cdk9 substrates

et al. 2016

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“…In our study, we observed that C/EBPα and β were significantly deregulated in tissues from Hnrnpk +/− mice. While recent ChIP-Seq studies in cell lines suggest hnRNP K may directly modulate C/EBPβ expression by specifically interacting with its promoter (Mikula et al, 2013), less is known regarding how hnRNP K regulates C/EBPα levels. Examination of the potential interaction between hnRNP K and the C/EBPα and C/EBPβ genes revealed that hnRNP K directly interacts with both genes.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, other studies have shown that hnRNP K represses C/EBPβ-mediated differentiation in the liver and that it regulates the expression of genes required for hematopoietic maturation (Miau et al, 1998; Ostareck et al, 1997). Together, these studies suggest hnRNP K plays a critical role in proliferation and differentiation and that deregulation of hnRNP K expression may promote tumorigenesis (Liu and Szaro, 2011; Mikula et al, 2013; van Domselaar et al, 2012; Wang et al, 2011). …”

Section: Introductionmentioning

confidence: 91%

hnRNP K Is a Haploinsufficient Tumor Suppressor that Regulates Proliferation and Differentiation Programs in Hematologic Malignancies

et al. 2015

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Summary hnRNP K regulates cellular programs and changes in its expression and mutational status have been implicated in neoplastic malignancies. To directly examine its role in tumorigenesis, we generated a mouse model harboring an Hnrnpk knock-out allele (Hnrnpk+/−). Hnrnpk haploinsufficiency resulted in reduced survival, increased tumor formation, genomic instability, and the development of transplantable hematopoietic neoplasms with myeloproliferation. Reduced hnRNP K expression attenuated p21 activation, downregulated C/EBP levels, and activated STAT3 signaling. Additionally, analysis of samples from primary acute myeloid leukemia patients harboring a partial deletion of chromosome 9 revealed a significant decrease in HNRNPK expression. Together, these data implicate hnRNP K in the development of hematological disorders and suggest hnRNP K acts as a tumor suppressor.

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“…For example, SRSF2 regulates transcriptional elongation in a sequence-specific manner via the 7SK complex that governs RNA polymerase II pause release 124 . Similarly, hnRNP A1, hnRNP A2 and hnRNP K are linked to cancer, and hnRNP A1 and A2 have reported roles in transcription elongation whereas hnRNP K is linked to transcription termination 125,126 . Many splicing factors co-transcriptionally associate with the C-terminal domain of RNA polymerase II, thereby coupling transcription, splicing, cleavage and polyadenylation (reviewed in 127 ).…”

Section: Connections To Other Cellular Processesmentioning

confidence: 99%

RNA splicing factors as oncoproteins and tumour suppressors

et al. 2016

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Preface The recent genomic characterization of cancers has revealed recurrent somatic point mutations and copy number changes affecting genes encoding RNA splicing factors. Initial studies of these ‘spliceosomal mutations’ suggest that the proteins bearing these mutations exhibit altered splice site and/or exon recognition preferences relative to their wild-type counterparts, resulting in cancer-specific mis-splicing. Such changes in the splicing machinery may create novel vulnerabilities in cancer cells that can be therapeutically exploited using compounds that can influence the splicing process. Further studies to dissect the biochemical, genomic, and biological effects of spliceosomal mutations are critical for the development of cancer therapies targeted to these mutations.

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Heterogeneous Nuclear Ribonucleoprotein (HnRNP) K Genome-wide Binding Survey Reveals Its Role in Regulating 3′-End RNA Processing and Transcription Termination at the Early Growth Response 1 (EGR1) Gene through XRN2 Exonuclease*

Cited by 30 publications

References 46 publications

P-TEFb regulation of transcription termination factor Xrn2 revealed by a chemical genetic screen for Cdk9 substrates

P-TEFb regulation of transcription termination factor Xrn2 revealed by a chemical genetic screen for Cdk9 substrates

hnRNP K Is a Haploinsufficient Tumor Suppressor that Regulates Proliferation and Differentiation Programs in Hematologic Malignancies

RNA splicing factors as oncoproteins and tumour suppressors

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