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The Trim33 ubiquitin ligase limits E2f4-dependent DNA replication [Cut&Run II]

ABSTRACT: Deregulation of RNA polymerase II (RNAPII) by oncoproteins, such as transcription factor Myc, interferes with DNA replication and is a major source of DNA damage and genomic instability. Ubiquitination is a key pathway controlling RNAPII activity via modification of RNAPII subunits or associated regulatory proteins. We uncover a mechanism for genome maintenance by ubiquitin ligase Trim33 and transcription factor E2f4. We show that Trim33 promotes E2f4 protein turnover, restricting interactions of E2f4 with chromatin and with the Recql DNA helicase. Replicative stress blunts Trim33-dependent regulation, which stimulates Recql recruitment to chromatin and facilitates recovery of DNA synthesis. Deletion of Trim33 triggers chronic recruitment of Recql and accelerates DNA replication under stress, accompanied by compromised DDR signaling and DNA repair. Depletion of Trim33 in Myc-overexpressing cells leads to accumulation of replication-associated DNA damage and delays Myc-driven tumorigenesis. We propose that the Trim33-E2f4-Recql axis provides a mechanism to control DNA replication at transcriptionally active chromatin to maintain genome integrity.

ORGANISM(S): Mus musculus

PROVIDER: GSE235671 | GEO | 2023/07/28

REPOSITORIES: GEO

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The Trim33 ubiquitin ligase limits E2f4-dependent DNA replication [DSB]

Project description:Deregulation of RNA polymerase II (RNAPII) by oncoproteins, such as transcription factor Myc, interferes with DNA replication and is a major source of DNA damage and genomic instability. Ubiquitination is a key pathway controlling RNAPII activity via modification of RNAPII subunits or associated regulatory proteins. We uncover a mechanism for genome maintenance by ubiquitin ligase Trim33 and transcription factor E2f4. We show that Trim33 promotes E2f4 protein turnover, restricting interactions of E2f4 with chromatin and with the Recql DNA helicase. Replicative stress blunts Trim33-dependent regulation, which stimulates Recql recruitment to chromatin and facilitates recovery of DNA synthesis. Deletion of Trim33 triggers chronic recruitment of Recql and accelerates DNA replication under stress, accompanied by compromised DDR signaling and DNA repair. Depletion of Trim33 in Myc-overexpressing cells leads to accumulation of replication-associated DNA damage and delays Myc-driven tumorigenesis. We propose that the Trim33-E2f4-Recql axis provides a mechanism to control DNA replication at transcriptionally active chromatin to maintain genome integrity.

2023-07-28 | GSE217521 | GEO

The Trim33 ubiquitin ligase limits E2f4-dependent DNA replication [RNA-seq]

2023-07-28 | GSE217523 | GEO

The Trim33 ubiquitin ligase limits E2f4-dependent DNA replication [Cut&Run]

2023-07-28 | GSE217520 | GEO

The Trim33 ubiquitin ligase limits E2f4-dependent DNA replication [ChIP-seq]

2023-07-28 | GSE217519 | GEO

A role for the Trim33 ubiquitin ligase in cellular response to replicative stress

Project description:Deregulation of RNA polymerase II (RNAPII) by oncoproteins, such as transcription factor Myc, interferes with DNA replication and is a major source of DNA damage and genomic instability. Ubiquitination is a key pathway controlling RNAPII activity via modification of RNAPII subunits or associated regulatory proteins. We uncover a mechanism for genome maintenance by ubiquitin ligase Trim33 and transcription factor E2f4. We show that Trim33 promotes E2f4 protein turnover, restricting interactions of E2f4 with chromatin and with the Recql DNA helicase. Replicative stress blunts Trim33-dependent regulation, which stimulates E2f4 and Recql recruitment to chromatin and facilitates recovery of DNA replication. Deletion of Trim33 triggers chronic recruitment of Recql to chromatin and accelerates DNA replication under stress, accompanied by compromised DDR signaling and DNA repair. Depletion of Trim33 in Myc-overexpressing cells leads to accumulation of replication-associated DNA damage and delays Myc-driven tumorigenesis. We propose that the Trim33-E2f4-Recql axis provides a mechanism to control DNA replication at transcriptionally active chromatin to maintain genome integrity.

2023-07-24 | PXD037854 | Pride

The dimeric deubiquitinase Usp28 integrates 53bp1 and Myc functions to limit DNA damage

Project description:The oncogenic transcription factor Myc is a pleiotropic regulator of RNA Polymerase II (RNAPII)-dependent transcription, DNA replication and DNA damage response pathways. Myc is stringently regulated by the ubiquitin system - for example, ubiquitination controls recruitment of the elongation factor Paf1c, which is critical for several Myc functions. Curiously, a key Myc-targeting deubiquitinase Usp28 also controls cellular response to DNA damage via the mediator protein 53bp1. Usp28 forms stable dimers, but the biological role of Usp28 dimerization is unknown. We show that dimerization limits Usp28 activity and restricts recruitment of Paf1c by Myc. Expression of monomeric Usp28 leads to ectopic Paf1c recruitment and resolution of transcription-replication conflicts, accelerating DNA synthesis. Strikingly, 53bp1 selectively interacts with and stabilizes dimeric Usp28 - depletion of 53bp1 favors formation of Usp28 monomers deregulating DNA replication. Genotoxic stress disrupts 53bp1-Usp28 complexes, promotes formation of Usp28 monomers and recruitment of Paf1 by Myc. This triggers ectopic DNA synthesis during early response to genotoxins, amplifying DNA damage. We propose that dimerization of Usp28 limits aberrant replication at transcriptionally active chromatin to maintain genome stability.

2023-11-09 | PXD037263 | Pride

TRANSCRIPTIONAL ACTIVATION BY E2F4 INDEPENDENT OF THE RB FAMILY

Project description:E2F transcription factors are central regulators of cell cycle progression and cell fate decisions in mammalian cells. E2F4 is a transcriptional repressor implicated in cell cycle arrest and whose repressive activity depends on its interaction with members of the RB family. E2F4 often represents the predominant E2F activity in cells. Here we show that E2F4 is important for the proliferation and the survival of mouse embryonic stem cells. In these cells, E2F4 acts in part as a transcriptional activator that promotes the expression of cell cycle genes. Importantly, this role for E2F4 is completely independent of the RB family. Accordingly, an unbiased analysis of the E2F4 interactome shows that E2F4 functionally interacts with chromatin regulators associated with gene activation in RB family-mutant cells. Taken together, our findings uncover a non-canonical role for E2F4 that reveal novel insights into the biology of rapidly dividing cell types.

2019-04-26 | PXD008796 | Pride

E2F4 and Myc ChIP-chip perfomed on Nimblegen hg17 ENCODE arrays

Project description:Identifying the chromosomal targets of transcription factors is important for reconstructing the transcriptional regulatory networks underlying global gene expression programs. ChIP-chip is a powerful technique to map chromosomal targets of transcription factors. We applied ChIP-chip to map downstream targets of the transcription factor E2F4 and c-Myc. E2F4 is a member of the E2F family of transcriptional regulators that functions as a repressor in quiescent and early G1 cells. c-Myc is a oncogenic transcription factor implicated in almost all aspects of tumorigenesis. We mapped E2F4 and c-Myc binding sites in 1% of the human genome using Nimblegen hg17 ENCODE arrays. Keywords: ChIP-chip

2007-01-20 | GSE6375 | GEO

MYC multimers shield stalled replication forks from RNA polymerase

Project description:Oncoproteins of the MYC family drive the development of numerous human tumors. In unperturbed cells, MYC proteins bind to virtually all active promoters and control transcription by RNA Polymerase II (RNAPII). MYC proteins can also coordinate transcription with DNA replication and promote the repair of transcription-associated DNA damage, but how they exert these mechanistically diverse functions is unknown. Here we show that MYC dissociates from many of its binding sites in active promoters and forms multimeric, often sphere-like structures in response to perturbation of transcription elongation, mRNA splicing or inhibition of the proteasome. Multimerization is accompanied by a global change in the MYC interactome towards proteins involved in transcription termination and RNA processing. MYC multimers accumulate on chromatin immediately adjacent to stalled replication forks and surround FANCD2, ATR and BRCA1 proteins, which are located at stalled forks. MYC multimerization is triggered in a HUWE1- and ubiquitylation-dependent manner. At active promoters, MYC multimers block antisense transcription and stabilize FANCD2 association with chromatin. This limits DNA double-strand break formation during S phase, suggesting that multimerization of MYC enables tumor cells to proliferate under stressful conditions.

2022-10-27 | PXD036674 | Pride

ChIP-seq analysis of E2f4, H3K4me2 and H3K27ac in the mouse livers

Project description:Arid1a is the subunit of SWI/SNF complex, which was reported to guide SWI/SNF to DNA. Here, we found that loss of Arid1a in the liver results in improved liver regeneration after partial hepatectomy.Genome-wide analysis showed that after hepatectomy,loss of Arid1a reduces the recruitment and activity of E2F4 on target promoters, resulting in expression programs that favor regeneration during injury. Correspondingly, these promoters showed increased H3k4me2 and H3k27ac marks, indicating de-repression of these E2f target genes. The post partial hepatectomy mice liver cells were fixed and isolated, analysis of genomic occupancy of E2f4,H3K4me2,H3K27ac in hepatocytes from Arid1a WT and Arid1a liver specific KO mice by ChIP-seq.

2016-03-30 | E-GEOD-76927 | biostudies-arrayexpress

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