The role of UBR5 in the PRC1-mediated transcriptional repression at damaged chromatin

UBR5 在 PRC1 介导的受损染色质转录抑制中的作用

• 批准号: 10092174
• 负责人: Sandra D. Westerheide
• 金额: $ 26.35万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092174
• 关键词: Area; Attention; BMI1 gene; Biochemical; Cell Nucleus; Cells; Cellular Stress; Chromatin; Complex; DNA Damage; DNA Double Strand Break; DNA Polymerase II; DNA biosynthesis; DNA lesion; DNA replication fork; DNA-Directed RNA Polymerase; Data; Deubiquitinating Enzyme; Development; Epigenetic Process; Gamma-H2AX; Gene Silencing; Genetic Transcription; Genome; Genotoxic Stress; Histones; Lead; Lesion; Malignant Neoplasms; Mediating; Mediator of activation protein; Metabolic; Modeling; Molecular; Molecular Chaperones; Monitor; Monoubiquitination; Oncogenic; Organism; Outcome Study; Output; PRC1 Protein; Pathway interactions; Polycomb; Polymerase; Process; Proliferating; Property; Proteome; RNA; RNA chemical synthesis; Radiation; Regulation; Role; Site; Small Interfering RNA; Structure; Testing; Transcription Elongation; Transcriptional Regulation; UV induced; Ubiquitin; Ubiquitination; Work; Zinc Fingers; base; cBioPortal; cancer cell; cancer type; epigenetic silencing; gene repression; genome integrity; histone modification; insight; member; programs; recruit; response; ubiquitin-protein ligase

Scientific Abstract Genome integrity is constantly threatened by various forms of genotoxic stresses, including radiation or endogenous metabolic products. Damaged DNA lesions in actively proliferating cells cause stalling of DNA replication polymerases as well as RNA polymerases, which can lead to replication fork arrest or transcriptional arrest, respectively. Understanding the cellular response to monitor and execute the polymerase stalling will give us better insight on how stressed cells, such as cancer cells, deal with the challenges. The BMI1-containing Polycomb complex (PRC1; Polycomb Repressive Complex 1) is an important regulator of epigenetic silencing programs during development, in part by inducing H2AK119 monoubiquitination (H2AK119-Ub) associated with repressed RNA Polymerase II (Pol II). Recently, the role of BMI1 in DNA damage response has gained much attention, but in what aspect and mechanism it participates in the process is unclear. In our preliminary studies, we identified UBR5 as a downstream factor whose chromatin recruitment is regulated by the BMI1-containing PRC1 complex. While transcription is repressed at UV-induced damaged sites on chromatin, depletion of the PRC1 members or UBR5 alone de-repressed transcription elongation at the damaged sites, suggesting that UBR5 functions in a linear pathway with PRC1 in inducing gene silencing at the lesions. We found that UBR5 interacts with BMI1 as well as histone chaperone complex FACT, and that UBR5 co-localizes with FACT component SPT16 to the UV-induced lesions in a BMI1-dependent manner. We further provide evidence that UBR5 directly ubiquitinates SPT16. Our evidence suggests a model that the BMI1-UBR5 axis antagonizes the FACT-dependent Pol II elongation upon UV insults. Based on these data, we propose a hypothesis that UBR5 is a key downstream effector of the PRC1- mediated gene silencing. The specific aims are to determine: 1) role of PRC1 and histone modification in UBR5 recruitment, 2) role of BMI1 and UBR5 in regulating transcriptional repression under DNA damaged or unperturbed conditions, 3) role of OTUD5 deubiquitinating enzyme in the UBR5 and PRC1-induced transcriptional repression at the lesions. The successful outcome of these studies will establish UBR5 as a key downstream mediator of the transcriptional regulation mediated by the PRC1 complex. The proposed work will fill the gap of important yet largely unknown function of the Polycomb complex in gene silencing, and will have an impact that advances the broader area of transcription, DNA damage response, and cancer development.

科学文摘

项目成果

Transcription-replication conflicts as a source of common fragile site instability caused by BMI1-RNF2 deficiency.

转录-复制冲突是 BMI1-RNF2 缺陷引起的常见脆弱位点不稳定的根源。

• DOI: 10.1371/journal.pgen.1008524
• 发表时间: 2020
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Sanchez,Anthony;deVivo,Angelo;Tonzi,Peter;Kim,Jeonghyeon;Huang,TonyT;Kee,Younghoon
• 通讯作者: Kee,Younghoon

Multifaceted roles of CCAR family proteins in the DNA damage response and cancer.

• DOI: 10.1038/s12276-023-01139-1
• 发表时间: 2024-02
• 期刊: EXPERIMENTAL AND MOLECULAR MEDICINE
• 影响因子: 12.8
• 作者: Lugano, D.;Barrett, L.;Westerheide, S. D.;Kee, Y.
• 通讯作者: Kee, Y.