Integrator complex and transcription regulation: Recent findings and pathophysiology

Rienzo, Monica; Casamassimi, Amelia

doi:10.1016/j.bbagrm.2016.07.008

Cited by 52 publications

(53 citation statements)

References 104 publications

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“…Eight subunits of the integrator complex are part of the molecular architecture of the pre‐mRNA 3′ processing complex (Y. Shi et al, ). The integrator complex binds to RNAP II (Baillat et al, ) and is involved in homeostatic transcription termination of specific genes, including non‐polyadenylated snRNAs (reviewed in J. Chen & Wagner, ; Rienzo & Casamassimi, ) and histone mRNAs (Skaar et al, ). These genes undergo a specialized processing of the 3′ ends of their RNAs (J. Chen et al, ; Ezzeddine et al, ; Marzluff, Wagner, & Duronio, ), and the disruption of mechanisms controlling snRNA transcription termination results into extended snRNAs with poly(A) tails in human cells (O'Reilly et al, ; Yamamoto et al, ).…”

Section: Cleavage and Polyadenylationmentioning

confidence: 99%

Connections between 3′ end processing and DNA damage response: Ten years later

Murphy

Kleiman

2019

WIREs RNA

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Ten years ago we reviewed how the cellular DNA damage response (DDR) is controlled by changes in the functional and structural properties of nuclear proteins, resulting in a timely coordinated control of gene expression that allows DNA repair. Expression of genes that play a role in DDR is regulated not only at transcriptional level during mRNA biosynthesis but also by changing steady‐state levels due to turnover of the transcripts. The 3′ end processing machinery, which is important in the regulation of mRNA stability, is involved in these gene‐specific responses to DNA damage. Here, we review the latest mechanistic connections described between 3′ end processing and DDR, with a special emphasis on alternative polyadenylation, microRNA and RNA binding proteins‐mediated deadenylation, and discuss the implications of deregulation of these steps in DDR and human disease. This article is categorized under: RNA Processing > 3′ End Processing RNA‐Based Catalysis > Miscellaneous RNA‐Catalyzed Reactions RNA in Disease and Development > RNA in Disease

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Section: Cleavage and Polyadenylationmentioning

confidence: 99%

Connections between 3′ end processing and DNA damage response: Ten years later

Murphy

Kleiman

2019

WIREs RNA

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“…First, most studies to date are based on constitutively expressed but RNA polymerase II (RNA Pol II)-dependent RNA species, such as mRNA transcripts of house-keeping genes and several miRNAs. RNA Pol II-dependent gene transcription is profoundly influenced by antemortem factors as well as postmortem situations, thus leading to large variations among individuals (Rienzo and Casamassimi, 2016; Zhang et al, 2016). Furthermore, standardization of postmortem RNA degradation profiles is important because different RNA transcripts show different degradation kinetics and steady-state expression levels among individuals, and even the overall RNA extraction efficacy is altered with PMI (González-Herrera et al, 2013; Koppelkamm et al, 2010); therefore, it is difficult to standardize or normalize the extent of RNA degradation in a quantitative manner.…”

Section: Discussionmentioning

confidence: 99%

Cell Death-Associated Ribosomal RNA Cleavage in Postmortem Tissues and Its Forensic Applications

Kim

Kyeong

et al. 2017

Molecules and Cells

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Estimation of postmortem interval (PMI) is a key issue in the field of forensic pathology. With the availability of quantitative analysis of RNA levels in postmortem tissues, several studies have assessed the postmortem degradation of constitutively expressed RNA species to estimate PMI. However, conventional RNA quantification as well as biochemical and physiological changes employed thus far have limitations related to standardization or normalization. The present study focuses on an interesting feature of the subdomains of certain RNA species, in which they are site-specifically cleaved during apoptotic cell death. We found that the D8 divergent domain of ribosomal RNA (rRNA) bearing cell death-related cleavage sites was rapidly removed during postmortem RNA degradation. In contrast to the fragile domain, the 5′ terminal region of 28S rRNA was remarkably stable during the postmortem period. Importantly, the differences in the degradation rates between the two domains in mammalian 28S rRNA were highly proportional to increasing PMI with a significant linear correlation observed in mice as well as human autopsy tissues. In conclusion, we demonstrate that comparison of the degradation rates between domains of a single RNA species provides quantitative information on postmortem degradation states, which can be applied for the estimation of PMI.

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“…The integrator complex (INT) is one of the major components of the RNA polymerase II mediated transcription machinery, playing a role in the regulation of most dependent genes [1,2,3]. This multiprotein consists of at least 14 different subunits, even though its structure and composition have not yet been fully characterized [3].…”

Section: Introductionmentioning

confidence: 99%

“…This multiprotein consists of at least 14 different subunits, even though its structure and composition have not yet been fully characterized [3]. It was originally discovered as a complex implicated in the 3′-end formation of noncoding uridine-rich small nuclear RNAs [1,4,5,6,7,8].…”

Section: Introductionmentioning

confidence: 99%

“…It was originally discovered as a complex implicated in the 3′-end formation of noncoding uridine-rich small nuclear RNAs [1,4,5,6,7,8]. However, in the last few years, many studies have promptly indicated broader functions for this complex, extending its role to other aspects of transcriptional regulation [2,3]. For instance, several experimental studies have also allowed for the assumption of a critical role for the INT complex in the activation of protein-coding genes, particularly in the pause-release and elongation of polymerase [9,10,11].…”

Section: Introductionmentioning

confidence: 99%

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Pan-Cancer Mutational and Transcriptional Analysis of the Integrator Complex

Federico

Rienzo

Abbondanza

et al. 2017

IJMS

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The integrator complex has been recently identified as a key regulator of RNA Polymerase II-mediated transcription, with many functions including the processing of small nuclear RNAs, the pause-release and elongation of polymerase during the transcription of protein coding genes, and the biogenesis of enhancer derived transcripts. Moreover, some of its components also play a role in genome maintenance. Thus, it is reasonable to hypothesize that their functional impairment or altered expression can contribute to malignancies. Indeed, several studies have described the mutations or transcriptional alteration of some Integrator genes in different cancers. Here, to draw a comprehensive pan-cancer picture of the genomic and transcriptomic alterations for the members of the complex, we reanalyzed public data from The Cancer Genome Atlas. Somatic mutations affecting Integrator subunit genes and their transcriptional profiles have been investigated in about 11,000 patients and 31 tumor types. A general heterogeneity in the mutation frequencies was observed, mostly depending on tumor type. Despite the fact that we could not establish them as cancer drivers, INTS7 and INTS8 genes were highly mutated in specific cancers. A transcriptome analysis of paired (normal and tumor) samples revealed that the transcription of INTS7, INTS8, and INTS13 is significantly altered in several cancers. Experimental validation performed on primary tumors confirmed these findings.

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Integrator complex and transcription regulation: Recent findings and pathophysiology

Cited by 52 publications

References 104 publications

Connections between 3′ end processing and DNA damage response: Ten years later

Connections between 3′ end processing and DNA damage response: Ten years later

Cell Death-Associated Ribosomal RNA Cleavage in Postmortem Tissues and Its Forensic Applications

Pan-Cancer Mutational and Transcriptional Analysis of the Integrator Complex

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