Promoters active in interphase are bookmarked during mitosis by ubiquitination

Arora, Mansi; Zhang, Jie; Heine, George F.; Özer, Gülçin; Liu, Hui Wen; Huang, Kun; Parvin, Jeffrey D.

doi:10.1093/nar/gks820

Cited by 8 publications

(16 citation statements)

References 61 publications

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“…Both histones H2A and H2B are ubiquitinated in S and G 2 phases, deubiquitinated in prophase and then reubiquinated in anaphase 49 . Also, the promoter of certain active genes remains ubiquitinated during the entire mitosis to facilitate their transcriptional reactivation in post-mitosis 50 . Although the ubiquitin ligase RNF20 is associated to genome ubiquitination, potentially TRIP12 also participates in this epigenetic modification of histones during mitosis.…”

Section: Discussionmentioning

confidence: 99%

The E3 ubiquitin ligase TRIP12 participates in cell cycle progression and chromosome stability

Larrieu

Brunet

Vargas

et al. 2020

Sci Rep

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Several studies have linked the E3 ubiquitin ligase TRIP12 (Thyroid hormone Receptor InteractingProtein 12) to the cell cycle. However, the regulation and the implication of this protein during the cell cycle are largely unknown. In this study, we show that TRIP12 expression is regulated during the cell cycle, which correlates with its nuclear localization. We identify an euchromatin-binding function of TRIP12 mediated by a N-terminal intrinsically disordered region. We demonstrate the functional implication of TRIP12 in the mitotic entry by controlling the duration of DNA replication that is independent from its catalytic activity. We also show the requirement of TRIP12 in the mitotic progression and chromosome stability. Altogether, our findings show that TRIP12 is as a new chromatin-associated protein with several implications in the cell cycle progression and in the maintenance of genome integrity.TRIP12 (Thyroid Hormone Receptor Interacting Protein 12) is a 225 kDa HECT (Homologous to the E6-AP Carboxyl Terminus) domain-containing E3 ubiquitin ligase. It is also known as ULF (Ubiquitin Ligase for ARF) 1 and UFD4 (Ubiquitin Fusion Degradation) in S. cerevisae 2 . TRIP12 contains protein interacting WWE (tryptophan and glutamate conserved residues) and β-ARM (β-Armadillo) domains 3 . Several functions are attributed to TRIP12. For instance, it ubiquitinates APP-BP1 (Amyloid Precursor Protein-Binding Protein 1) and BAF57 (Brg1-Associated Factor 57) turn over and is therefore described as a sensor of SWI/SNF (SWItch/Sucrose Non-Fermentable) complex integrity 4,5 . TRIP12 is also known to control the histone ubiquitination after DNA breakage 6 and to contribute to p14/ARF (Alternate Reading Frame) degradation in response to DNA damage 7 . TRIP12 ensures the proteolysis of ASLX1 (Additional Sex Combs Like 1, Transcriptional Regulator), a regulatory component of the ubiquitin hydrolase BAP1 (BRCA1 Associated Protein 1) 8 . We showed that TRIP12 is implicated in the proteasome-mediated degradation of the transcription factor PTF1a (Pancreas specific Transcription Factor 1a) that plays an important role in the maintenance of the acinar phenotype in human pancreas 9 . TRIP12 is essential for cell viability as a homozygous mutation that disrupts the ubiquitin ligase activity leads to murine embryonic lethality 10 . Importantly, TRIP12 plays an important role in the cell cycle. For instance, Trip12 mt/mt ES cells display reduced growth with increased expression of the p16/CDKN2A gene and an accumulation in G 2 /M phase 10 . Moreover, by controlling the tumor suppressor protein p14/ARF, TRIP12 impacts TP53 protein level, a major regulator of the cell cycle 11 . TRIP12 expression is altered in several types of cancer, such as breast and pancreatic cancer 11 . High expression of TRIP12 is associated with poor prognosis in hepatocellular carcinoma after surgical resection 12 . TRIP12 is involved in radio-sensitization of head and neck squamous carcinoma 13 . TRIP12 mutations are also related to autism disorders 14 and intel...

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Section: Discussionmentioning

confidence: 99%

The E3 ubiquitin ligase TRIP12 participates in cell cycle progression and chromosome stability

Larrieu

Brunet

Vargas

et al. 2020

Sci Rep

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“…This novel role of ubiquitin was first identified through a variant of ChIP-seq experiments that found ubiquitin present on certain sites during mitosis that were previously not described [108]. Those experiments showed that during interphase, ubiquitin was present on the chromatin of transcribed regions of transcriptionally active genes, consistent with the known function of PAF1C.…”

Section: Ubiquitin As a Mitotic Bookmarkmentioning

confidence: 65%

“…The fundamental difference between interphase and mitosis was a shift of the ubiquitin detected near promoters of the same genes that were previously ubiquitinated on their transcribed regions. For example [109], the GAPDH gene is heavily ubiquitinated over the gene body during G1 ( Figure 4A, indicated in blue), while during mitosis that ubiquitination over the gene body is absent but ubiquitination is detected over the promoter (Figure 4A, gold) [108]. The ubiquitinated promoter sites were consistently ubiquitinated at 150 bp upstream of the transcription start sites, suggesting a specific function relating each of these promoters.…”

Section: Ubiquitin As a Mitotic Bookmarkmentioning

confidence: 98%

Processes that Regulate the Ubiquitination of Chromatin and Chromatin-Associated Proteins

Hare¹,

Parvin²

2019

Ubiquitin Proteasome System - Current Insights Into Mechanism Cellular Regulation and Disease

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Ubiquitin is a post-translational modification important for many different processes in the cell, including antigen presentation and proteosomal degradation of proteins. It is heavily involved in the regulation of chromatin and the proteins that control chromatin-related processes. In this review, we will focus on ubiquitinbased chromatin regulation involved in four different processes. The first is DNA double strand break (DSB) repair and the role that ubiquitin plays in not just recruiting and stimulating DSB repair, but also the choice of pathway. The second is the PAF1 complex, which is involved in transcriptional elongation and interacts with RNAPII. The third is polycomb repressive complexes, specifically polycomb repressive complex 1, which utilizes ubiquitin to repress constitutively inactive genes. The last role of ubiquitin discussed is ubiquitin as a mitotic bookmark, which serves to provide a record of-active genes as cells transit mitosis. Each of these processes has independent pathways, but each is necessary for proper cellular function and organismal health.

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“…Leukemia cells transformed by MLL-FP are more dependent on RNF20 to maintain their oncogenic transcriptional program than normal hematopoietic cells, which may relate to the altered transcriptional effector activity brought by the MLL-FP [55]. In addition to influencing HOX gene expression, RNF20 is required to mark genes in mitosis for sustained expression in interphase [56] and for genomic stability in other settings [57]. Overall, the PAFc and RNF20 appear to function to ensure high-level expression of genes critical for MLL-FP–initiated leukemogenesis.…”

Section: Constitutive Protein Interactorsmentioning

confidence: 99%

Two decades of leukemia oncoprotein epistasis: the MLL1 paradigm for epigenetic deregulation in leukemia

Ernst

2014

Experimental Hematology

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MLL1, located on human chromosome 11, is disrupted in distinct recurrent chromosomal translocations in several leukemia subsets. Studying the MLL1 gene and its oncogenic variants has provided a paradigm for understanding cancer initiation and maintenance through aberrant epigenetic gene regulation. Here we review the historical development of model systems to recapitulate oncogenic MLL1-rearrangement (MLL-r) alleles encoding mixed-lineage leukemia fusion proteins (MLL-FPs) or internal gene rearrangement products. These largely mouse and human cell/xenograft systems have been generated and used to understand how MLL-r alleles affect diverse pathways to result in a highly penetrant, drug-resistant leukemia. The particular features of the animal models influenced the conclusions of mechanisms of transformation. We discuss significant downstream enablers, inhibitors, effectors, and collaborators of MLL-r leukemia, including molecules that directly interact with MLL-FPs and endogenous mixed-lineage leukemia protein, direct target genes of MLL-FPs, and other pathways that have proven to be influential in supporting or suppressing the leukemogenic activity of MLL-FPs. The use of animal models has been complemented with patient sample, genome-wide analyses to delineate the important genomic and epigenomic changes that occur in distinct subsets of MLL-r leukemia. Collectively, these studies have resulted in rapid progress toward developing new strategies for targeting MLL-r leukemia and general cell-biological principles that may broadly inform targeting aberrant epigenetic regulators in other cancers.

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Promoters active in interphase are bookmarked during mitosis by ubiquitination

Cited by 8 publications

References 61 publications

The E3 ubiquitin ligase TRIP12 participates in cell cycle progression and chromosome stability

The E3 ubiquitin ligase TRIP12 participates in cell cycle progression and chromosome stability

Processes that Regulate the Ubiquitination of Chromatin and Chromatin-Associated Proteins

Two decades of leukemia oncoprotein epistasis: the MLL1 paradigm for epigenetic deregulation in leukemia

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