Assembly and epigenetic inheritance of the human centromere

人类着丝粒的组装和表观遗传

• 批准号: 10463586
• 负责人: Daniel Richard Foltz
• 金额: $ 33.18万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10463586
• 关键词: Address; Affect; Aneuploidy; Binding; Biological; Biology; CRISPR/Cas technology; Cell Cycle; Cell division; Centromere; Characteristics; Chromatin; Chromatin Modeling; Chromosome Arm; Chromosome Segregation; Chromosomes; Complex; DAXX gene; DNA; DNA Sequence; DNA biosynthesis; DNA replication fork; Data; Deposition; Ensure; Epigenetic Process; Funding; Genome; Genomic Instability; Genomics; Grant; Histone H3; Histones; Human; Individual; Kinetochores; Lead; MCM2 gene; Maintenance; Malignant Neoplasms; Mediating; Methods; Mitosis; Mitotic; Mitotic spindle; Molecular; Molecular Chaperones; Nature; Nucleosomes; Oncogenes; Phase; Post-Translational Protein Processing; Process; Proteins; Role; S phase; Satellite DNA; Signal Transduction; Site; Specific qualifier value; Variant; Work; centromere protein A; chromosome missegregation; chromosome movement; experimental study; inhibitor; novel; recruit; replication stress

Chromosome missegregation and aneuploidy are commons characteristics of cancer. Centromeres are chromosomal loci that define the site of kinetochore formation and ensure faithful chromosome segregation during mitosis. Centromeric identity is epigenetically specified by the incorporation of CENP-A nucleosomes, independent of DNA sequence. Because of the chromatin nature of the centromere, the processes that govern CENP-A nucleosome assembly and nucleosome stability are essential to the maintenance of centromere specification. New CENP-A must be added to the centromere in a consistent and faithful manner during each cell cycle to maintain centromeric chromatin and centromere identity. New CENP-A nucleosomes are added to the centromere during G1 by the CENP-A specific chaperone HJURP, that is recruited to centromere by the Mis18 complex. Although unlike canonical histone H3, new CENP-A is not deposited during DNA replication; however, CENP-A nucleosomes are retained at the centromere during DNA replication to ensure the transmittance of the centromeric locus. The mechanism by which CENP-A nucleosomes are stably retained when chromatin is disassembled during DNA replication will be addressed in this application. Centromeres are located within the alpha-satellite DNA repeats in most individuals; however, several neocentromeres have been identified where centromere proteins relocate and function at non-centromeric sites. This application will address the ability of non-centromeric sites to acquire centromeric identity in order to understand the chromatin and genomic contributions to centromere function.

染色体错误分离和非整倍性是癌症的常见特征。 着丝粒是定义着丝粒形成位点的染色体位点 确保有丝分裂过程中染色体的忠实分离。着丝粒身份是 通过掺入 CENP-A 核小体进行表观遗传指定，独立于 DNA 序列。由于着丝粒的染色质性质，该过程 控制 CENP-A 核小体组装，核小体稳定性对于 着丝粒规格的维持。新的CENP-A必须添加到着丝粒上 在每个细胞周期中以一致和忠实的方式维持着丝粒 染色质和着丝粒的身份。新的CENP-A核小体被添加到 G1 期间着丝粒由 CENP-A 特异性伴侣 HJURP 招募， 着丝粒由 Mis18 复合体组成。尽管与经典组蛋白 H3 不同，新的 CENP-A DNA复制过程中不沉积；然而，CENP-A核小体保留在 DNA复制过程中的着丝粒，以确保着丝粒的传递性 轨迹。 CENP-A核小体稳定保留的机制 本申请将解决 DNA 复制过程中染色质被分解的问题。 大多数个体的着丝粒位于 α 卫星 DNA 重复序列内； 然而，已经鉴定出一些新着丝粒，其中着丝粒蛋白 在非着丝粒位点重新定位并发挥作用。该应用程序将解决以下能力 非着丝粒位点以获得着丝粒身份以了解 染色质和基因组对着丝粒功能的贡献。

项目成果

Posttranslational modifications of CENP-A: marks of distinction.

• DOI: 10.1007/s00412-018-0665-x
• 发表时间: 2018-09
• 期刊: Chromosoma
• 影响因子: 1.6
• 作者: Srivastava S;Foltz DR
• 通讯作者: Foltz DR

Nucleoli and the nucleoli-centromere association are dynamic during normal development and in cancer.

• DOI: 10.1091/mbc.e22-06-0237
• 发表时间: 2023-04-01
• 期刊: MOLECULAR BIOLOGY OF THE CELL
• 影响因子: 3.3
• 作者: Rodrigues, Aaron;MacQuarrie, Kyle L.;Freeman, Emma;Lin, Alicia;Willis, Alexander B.;Xu, Zhaofa;Alvarez, Angel A.;Ma, Yongchao;White, Bethany E. Perez;Foltz, Daniel R.;Huang, Sui
• 通讯作者: Huang, Sui

The histone H3/H4 chaperone CHAF1B prevents the mislocalization of CENP-A for chromosomal stability.

• DOI: 10.1242/jcs.260944
• 发表时间: 2023-05-15
• 期刊: Journal of cell science
• 影响因子: 4

Mislocalization of centromeric histone H3 variant CENP-A contributes to chromosomal instability (CIN) in human cells.

着丝粒组蛋白 H3 变体 CENP-A 的错误定位会导致人类细胞染色体不稳定 (CIN)。

• DOI: 10.18632/oncotarget.18108
• 发表时间: 2017-07-18
• 期刊: Oncotarget
• 作者: Shrestha RL;Ahn GS;Staples MI;Sathyan KM;Karpova TS;Foltz DR;Basrai MA
• 通讯作者: Basrai MA

CENP-A overexpression promotes aneuploidy with karyotypic heterogeneity.

• DOI: 10.1083/jcb.202007195
• 发表时间: 2021-04-05
• 期刊: The Journal of cell biology
• 作者: Shrestha RL;Rossi A;Wangsa D;Hogan AK;Zaldana KS;Suva E;Chung YJ;Sanders CL;Difilippantonio S;Karpova TS;Karim B;Foltz DR;Fachinetti D;Aplan PD;Ried T;Basrai MA
• 通讯作者: Basrai MA