Nudt21 Controls Cell Fate by Connecting Alternative Polyadenylation to Chromatin Signaling

Brumbaugh, Justin; Stefano, Bruno Di; Yang, Guolai; Borkent, Marti; Forouzmand, Elmira; Clowers, Katie J.; Ji, Fei; Schwarz, Benjamin A.; Kalocsay, Marian; Elledge, Stephen J.; Chen, Yue; Sadreyev, Ruslan I.; Gygi, Steven P.; Hu, Guang; Shi, Yongsheng; Hochedlinger, Konrad

doi:10.1016/j.cell.2017.11.023

Cited by 125 publications

(114 citation statements)

References 63 publications

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“…While only 25 kDa in size, NUDT21 forms a number of direct protein interactions with key RNA processing components, including Poly(A) Polymerase 34 . These findings support the role of NUDT21 as an emerging master regulator of alternative cleavage and polyadenylation site choice in mammals 35,36 .…”

Section: Post-transcriptional Cleavage and Polyadenylation Of Messengsupporting

confidence: 79%

Targeted Cleavage and Polyadenylation of RNA by CRISPR-Cas13

Poosala

Lindley

et al. 2019

Preprint

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Post-transcriptional cleavage and polyadenylation of messenger and long noncoding RNAs is coordinated by a supercomplex of ~20 individual proteins within the eukaryotic nucleus1,2. Polyadenylation plays an essential role in controlling RNA transcript stability, nuclear export, and translation efficiency3–6. More than half of all human RNA transcripts contain multiple polyadenylation signal sequences that can undergo alternative cleavage and polyadenylation during development and cellular differentiation7,8. Alternative cleavage and polyadenylation is an important mechanism for the control of gene expression and defects in 3’ end processing can give rise to myriad human diseases9,10. Here we show that fusion of catalytically dead Cas13 to a single mammalian polyadenylation factor, Nudix hydrolase 21 (NUDT21), allows for site-specific CRISPR-Cas13-guided cleavage and polyadenylation of RNA in mammalian cells. This approach, which we named Postscriptr, can be utilized for the non-genomic manipulation of gene expression and may have potential future therapeutic applications for treating human RNA processing diseases.

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Section: Post-transcriptional Cleavage and Polyadenylation Of Messengsupporting

confidence: 79%

Targeted Cleavage and Polyadenylation of RNA by CRISPR-Cas13

Poosala

Lindley

et al. 2019

Preprint

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“…In humans, a majority of genes (51-79%) express alternative 3’-UTRs, demonstrating the widespread nature of this process 24 . Indeed, APA has important roles in muscle stem cell function, cell proliferation, chromatin signaling, pluripotent cell fate, cellular senescence and other physiological processes 25–29 . Recently, dysregulation of APA has gained recognition as a driver of tumorigenesis 28,30–33 .…”

Section: Introductionmentioning

confidence: 99%

Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma

Venkat

Tisdale

Schwarz

et al. 2019

Preprint

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Alternative polyadenylation (APA) is a gene regulatory process that dictates mRNA 3’-UTR length, resulting in changes in mRNA stability and localization. APA is frequently disrupted in cancer and promotes tumorigenesis through altered expression of oncogenes and tumor suppressors. Pan-cancer analyses have revealed common APA events across the tumor landscape; however, little is known about tumor type-specific alterations that may uncover novel events and vulnerabilities. Here we integrate RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project and The Cancer Genome Atlas (TCGA) to comprehensively analyze APA events in 148 pancreatic ductal adenocarcinomas (PDAs). We report widespread, recurrent and functionally relevant 3’-UTR alterations associated with gene expression changes of known and newly identified PDA growth-promoting genes and experimentally validate the effects of these APA events on expression. We find enrichment for APA events in genes associated with known PDA pathways, loss of tumor-suppressive miRNA binding sites, and increased heterogeneity in 3’-UTR forms of metabolic genes. Survival analyses reveal a subset of 3’-UTR alterations that independently characterize a poor prognostic cohort among PDA patients. Finally, we identify and validate the casein kinase CK1α as an APA-regulated therapeutic target in PDA. Knockdown or pharmacological inhibition of CK1α attenuates PDA cell proliferation and clonogenic growth. Our single-cancer analysis reveals APA as an underappreciated driver of pro-tumorigenic gene expression in PDA via the loss of miRNA regulation.

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“…Since RBPs have diverse functions in posttranscriptional gene regulation, their appropriate expression is critical to many biological processes, such as cell differentiation, proliferation and cell fate transition. For example, the RBP genes MBNL1 and MBNL2 control splicing of the 18th exon of transcription factor FOXP1 to switch pluripotency and reprogramming of embryonic stem cells (ESCs), while the RBP gene NUDT21 directs alternative polyadenylation of thousands of transcripts to control cell fate transition of ESCs (Gabut et al 2011;Han et al 2013;Brumbaugh et al 2018). Dysregulation of RBPs could cause severe human diseases, including cancer (Yeo 2014).…”

Section: Introductionmentioning

confidence: 99%

Pan-cancer analysis of RNA binding proteins (RBPs) reveals the involvement of the core pre-mRNA splicing and translation machinery in tumorigenesis

Zhang

et al. 2018

Preprint

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RNA binding proteins (RBPs) are key regulators of posttranscriptional processes such as RNA maturation, transport, localization, turnover and translation. Despite their dysregulation in various diseases including cancer, the landscape of RBP expression and regulatory mechanisms in human cancer has not been well characterized. Here, we analyzed mRNA expression of 1487 RBPs in ~6700 clinical samples across 16 human cancer types and found that there were significantly more upregulated RBPs than downregulated ones in tumors when compared to their adjacent normal tissues. Across almost all of the 16 cancer types, 109 RBPs were consistently upregulated (cuRBPs) while only 41 RBPs were consistently downregulated (cdRBPs). Integrating expression with the copy number and DNA methylation data, we found that the overexpression of cuRBPs is largely associated with the amplification of copy number, whereas the downregulation of cdRBPs may be a result of epigenetic silencing mediated by DNA methylation. Furthermore, our results indicated that cuRBPs could work together to promote cancer progression potentially through the involvement of splicing and translation machinery, while cdRBPs might function independently to suppress tumorigenesis.Additionally, we focused on colon cancer and identified several novel potential oncogenic RBPs, such as PABPC1L which might promote cancer development via regulating the core splicing machinery. In summary, we showed distinct expression landscapes, regulatory mechanisms and characteristics of cuRBPs and cdRBPs and implicated several novel RBPs in cancer pathogenesis. Moreover, our results suggest that the involvement of the core pre-mRNA splicing and translation machinery could be critical in tumorigenesis.

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Nudt21 Controls Cell Fate by Connecting Alternative Polyadenylation to Chromatin Signaling

Cited by 125 publications

References 63 publications

Targeted Cleavage and Polyadenylation of RNA by CRISPR-Cas13

Targeted Cleavage and Polyadenylation of RNA by CRISPR-Cas13

Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma

Pan-cancer analysis of RNA binding proteins (RBPs) reveals the involvement of the core pre-mRNA splicing and translation machinery in tumorigenesis

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