Regulation of mitotic chromosomes

有丝分裂染色体的调控

基本信息

批准号：
10396982
负责人：
Hironori Funabiki
金额：
$ 83.06万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10396982
关键词：
Affect Antimitotic Agents Binding Proteins Biochemistry Cancer Etiology Cell Aging Cell Death Cells Centromere Chemotherapy-Oncologic Procedure Chromatin Chromosome Segregation Chromosomes Clinical Treatment Competitive Binding Complex Congenital Abnormality DNA Development Event Face Failure Genetic Transcription Genomic DNA HELLS gene Histones Human Image Immune Immunity Immunodeficiency and Cancer Innate Immune System Kinetochores Lead Mediating Methods Microtubules Mitosis Mitotic Mitotic Chromosome Mitotic Spindle Apparatus Molecular Morphology Nucleosomes Organism Paclitaxel Regulation Repetitive Sequence Research Role Satellite DNA Structure Syndrome Testing Transcriptional Regulation Xenopus cancer cell cell growth chromatin protein cytotoxic developmental disease egg novel preservation programs segregation sensor tumor

项目摘要

Project Summary Proper chromosome segregation during mitosis is fundamental to cell growth and organism development. Failures in this step lead to developmental diseases, immunodeficiency, and cancers. My research program aims to reveal molecular mechanisms critical for chromosome segregation and elucidate the consequences of their failures, which can be exploited to enhance the efficacy of chemotherapeutic treatments. 1) Roles of nucleosome regulators in chromosome segregation: During mitosis, chromosomes dramatically change their functions and morphology to support their segregation. Chromosomes become condensed, while promoting formation of mitotic apparatuses, such as kinetochores and spindle microtubules. Although histones are the most abundant chromatin proteins, the importance of histones in transcriptional regulation makes it challenging to dissect their direct roles in mitosis. Our lab has established a novel method to manipulate histones and evaluate their consequences using Xenopus egg extracts, which recapitulates a variety of chromatin events independently of transcription. We discovered that the chromosomal passenger complex (CPC) must interact with both nucleosomes and microtubules to support spindle assembly. As chromatin proteins regulated by the CPC, we discovered a novel nucleosome-remodeling complex composed of HELLS and CDCA7, relevant to Centromere instability and Facial anomalies (ICF) syndrome. By dissecting the roles of HELLS-CDCA7 and other nucleosome regulators, we will investigate the poorly understood mechanisms and functional significance of mitosis-specific control of nucleosome dynamics and functions. 2) Mechanisms that maintain human centromere integrity: Human centromeres, where kinetochores assemble to capture microtubules, are composed of a long array of repetitive element, α-satellite DNA. We have shown that α-satellite repetitive arrangement becomes unstable in cancer cells and during cellular senescence, and that centromere-binding proteins are important for preserving this arrangement. We will dissect mechanisms that maintain integrity of centromere-associated repetitive elements. 3) Recognition of mitotic failures by the innate immune system: We hypothesize that nucleosomes act as a hallmark that distinguish between genomic DNAs and foreign or aberrant DNAs. Consistent with this idea, we demonstrated that the nucleosome competitively binds and inhibits DNA-induced stimulation of the cytoplasmic DNA sensor, cGAS, a component of the innate immune system. We showed that during extended mitosis, cGAS is slowly activated and induce cell death. Cells that do not express cGAS are less prone to die during mitotic arrest induced by taxol, which is frequently used in cancer chemotherapy. Thus, cGAS expression level could be a predictor of the efficacy of taxol, and cGAS mediated-immunity may affect cytotoxic effect of taxol on tumors. We will investigate mechanisms behind cGAS-induced cell death and its relevance to clinical treatment with taxol.

项目概要有丝分裂期间适当的染色体分离是细胞生长和生物体发育的基础。这一步的失败会导致发育性疾病、免疫缺陷和癌症。旨在揭示对染色体分离至关重要的分子机制并阐明其后果他们的失败，可以用来提高化疗的疗效。 1) 核小体调节因子在染色体分离中的作用：在有丝分裂过程中，染色体急剧分离改变它们的功能和形态以支持它们的分离，同时。促进有丝分裂装置的形成，例如动粒和纺锤体微管。是最丰富的染色质蛋白，组蛋白在转录调控中的重要性使其剖析它们在有丝分裂中的直接作用具有挑战性，我们的实验室已经建立了一种新的操纵方法。组蛋白并使用非洲爪蟾卵提取物评估其后果，该提取物概括了各种我们发现染色体过客复合体独立于转录。 (CPC) 必须与核小体和微管相互作用以支持纺锤体组装。受CPC调节的蛋白质，我们发现了一种由HELLS组成的新型核小体重塑复合物和CDCA7，与着丝粒不稳定和面部异常（ICF）综合征相关。 HELLS-CDCA7 和其他核小体调节因子，我们将研究人们知之甚少的机制核小体动力学和功能的有丝分裂特异性控制的功能意义。 2）维持人类着丝粒完整性的机制：人类着丝粒，着丝粒聚集的地方捕获微管的细胞是由一长串重复元件组成的，我们已经证明了α-卫星DNA。 α-卫星重复排列在癌细胞和细胞衰老过程中变得不稳定，并且着丝粒结合蛋白对于维持这种排列很重要，我们将剖析机制。保持着丝粒相关重复元件的完整性。 3）先天免疫系统对有丝分裂失败的识别：我们发现核小体充当区分基因组 DNA 和外来或异常 DNA 的标志与这一想法一致，我们。核小体竞争性结合并抑制 DNA 诱导的细胞质刺激 DNA 传感器 cGAS，先天免疫系统的一个组成部分我们发现，在延长的有丝分裂过程中， cGAS 被缓慢激活并诱导细胞死亡，不表达 cGAS 的细胞在此过程中不易死亡。常用于癌症化疗的紫杉醇诱导有丝分裂停滞，因此 cGAS 表达水平。可能是紫杉醇疗效的预测因子，cGAS介导的免疫可能影响紫杉醇的细胞毒作用我们将研究 cGAS 诱导细胞死亡的机制及其与临床的相关性。用紫杉醇治疗。