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Regulation of mitotic chromosomes

有丝分裂染色体的调控

基本信息

批准号：
10611986
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/10611986
关键词：
Affect Antimitotic Agents Binding Proteins Biochemistry Cancer Etiology Cell Aging Cell Death Induction Cells Centromere Chemotherapy-Oncologic Procedure Chromatin Chromosome Segregation Chromosomes Clinical Treatment Competitive Binding Complex Congenital Abnormality Cytoplasm DNA Development Event Face Failure Genetic Transcription Genomic DNA HELLS gene Histones Human Image Immune Immunity Immunologic Deficiency Syndromes Innate Immune System Kinetochores Lead Malignant Neoplasms 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 Therapeutic 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.

项目总结