The role of macroH2A variants in cancer and senescence

MacroH2A 变异在癌症和衰老中的作用

• 批准号: 10132248
• 负责人: MATTHEW J GAMBLE
• 金额: $ 38.2万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-04 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10132248
• 关键词: ATM Signaling Pathway; ATM activation; Acetylation; Affect; Alternative Splicing; Binding; Bladder; Breast; Bypass; C-terminal; Cell Differentiation process; Cell physiology; Cells; Chromatin; Colon; DNA Damage; DNA Polymerase II; DNA Repair; Data; Development; EP300 gene; Endometrium; Event; Excision; Family; Feedback; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Techniques; Genetic Transcription; Genomics; Goals; Grant; Histone H2A; Histones; Knowledge; Lead; Ligand Binding Domain; Lung; Malignant Neoplasms; Mediating; Molecular Conformation; Monitor; Oncogenes; Oncogenic; Ovary; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerases; Process; RNA; RNA Splicing; Regulation; Role; SECTM1 gene; Signal Transduction; Testing; Testis; Transcriptional Regulation; Tumor Suppression; Variant; ataxia telangiectasia mutated protein; biological adaptation to stress; cancer cell; cancer type; endoplasmic reticulum stress; flexibility; gene repression; genome-wide; innovation; mRNA Precursor; melanocyte; mutant; novel; recruit; response; reverse genetics; senescence; small hairpin RNA; stem cells; transcription factor; tumor; tumorigenesis

Project Summary The macroH2A1-type histone variants (which include macroH2A1.1 and macroH2A1.2) have roles in tumor suppression, senescence, activation and repression of transcription, promotion of DNA repair and suppression of the reprogramming of differentiated cells into stem cells. MacroH2As are typified by a histone H2A-like region fused by a flexible linker to a C-terminal macrodomain, a ligand-binding domains whose functions are modulated by binding to poly(ADP-ribose) produced by a family of poly(ADP-ribose) polymerases. MacroH2A1 regulates the expression of genes found within its large chromatin domains which can span hundreds of kilobases. MacroH2A1 also plays a critical role in regulating gene expression during oncogene-induced senescence, an important tumor suppressive mechanisms. Interestingly, during senescence an ER stress-dependent mechanism requiring the DNA damage signaling kinase ATM leads to genome-wide changes in macroH2A1 genomic distribution which resemble that of cancer cells. Through changes in its expression and/or alterations in its genomic localization, disruption of macroH2A1’s tumor suppressive functions is common in cancer; alterations of macroH2A transcription and splicing have been observed in a variety of cancers including those of lung, breast, colon, ovaries, endometrium, bladder, testicles, and melanocytes. Consistently, macroH2A1 loss in primary cells is sufficient to trigger an oncogenic gene expression profile. The overall goals of this project are to elucidate the function of macroH2A1in the regulation of gene expression in normal and senescent cells and to determine how dysregulation of macroH2A1 function contributes to alterations in gene expression that allow senescence-bypass and oncogenesis. A variety of innovative reverse genetics, pharmacological and genome-wide approaches will be used in the pursuit of these goals. The first aim will determine the mechanisms by which macroH2A1 variants regulate transcription in normal and senescent cells. The second aim will determine the mechanism of ATM activation and macroH2A1 mobilization in response to ER stress during senescence. The third aim will determine the mechanism by with RNA Pol II elongation rate regulates macroH2A1 splicing. The knowledge about macroH2A1-mediated regulation of gene expression, genomic localization and macroH2A1 splicing regulation gained from this proposal will help to explain how macroH2A1 function becomes dysregulated during oncogenesis.

项目摘要 macroH 2A 1型组蛋白变体（包括macroH2A1.1和macroH2A1.2）在以下方面发挥作用： 肿瘤抑制、衰老、转录的激活和抑制、DNA修复的促进和 抑制分化细胞重编程为干细胞。大分子H2 As的典型代表是 组蛋白H2 A样区通过柔性接头融合到C-末端宏结构域、配体结合结构域 其功能通过与聚（ADP-核糖）家族产生的聚（ADP-核糖）结合而调节， 聚合酶MacroH 2A 1调节在其大染色质结构域内发现的基因的表达， 可以跨越数百个领域。MacroH 2A 1也在调节基因表达中起关键作用， 癌基因诱导的衰老是一种重要的肿瘤抑制机制。有趣的是，在 衰老是一种ER应激依赖性机制，需要DNA损伤信号激酶ATM， macroH 2A 1基因组分布的全基因组变化类似于癌细胞的变化。通过 其表达的变化和/或其基因组定位的改变，macroH 2A 1肿瘤的破坏 抑制功能在癌症中是常见的; macroH 2A转录和剪接的改变已经被发现， 在多种癌症中观察到，包括肺癌、乳腺癌、结肠癌、卵巢癌、子宫内膜癌、膀胱癌， 睾丸和黑色素细胞一致地，原代细胞中的macroH 2A 1损失足以触发 致癌基因表达谱。 本课题的总体目标是阐明macroH 2A 1在基因调控中的作用， 在正常和衰老细胞中的表达，并确定macroH 2A 1功能的失调 有助于基因表达的改变，从而允许衰老旁路和肿瘤发生。各种 创新的反向遗传学、药理学和全基因组方法将用于寻求 这些目标。第一个目标是确定macroH 2A 1变体调节细胞凋亡的机制。 在正常和衰老细胞中的转录。第二个目标将决定ATM的机制 激活和macroH 2A 1动员响应ER应激衰老过程中。第三个目标将 通过与RNA Pol II的延伸速率调节macroH 2A 1剪接来确定机制。知识 关于macroH 2A 1介导的基因表达调控、基因组定位和macroH 2A 1剪接 从这个建议中获得的调节将有助于解释macroH 2A 1功能如何变得失调 在肿瘤形成过程中。