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体是癌症的共同特征。 着丝粒是定义着丝粒形成的位置的染色体位置。 在有丝分裂过程中确保忠实的染色体分离。着丝粒同一性是 由CENP-A核小体的掺入而表观遗传学指定，独立于 DNA序列。由于着丝粒的染色质性质， 控制CENP-A核小体组装和核小体稳定性对 着丝粒规格的维护。着丝粒中必须添加新的CENP-A 在每个细胞周期中以一致和忠实的方式保持着丝粒 染色质和着丝粒的同一性。新的CENP-A核小体增加到 由CENP-A特异性伴侣HJURP在G1期的着丝粒，它被招募到 着丝粒由Mis18复合体产生。尽管与典型的组蛋白H3不同，新的CENP-A 在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，以确保着丝粒的透过性 轨迹。CENP-A核小体被稳定保留的机制 DNA复制过程中染色质的分解将在本申请中解决。 着丝粒位于大多数个体的阿尔法卫星DNA重复序列中； 然而，几个新着丝粒已经被鉴定出在着丝粒蛋白 在非着丝粒部位重新定位并发挥作用。此应用程序将解决以下能力 非着丝粒位点获得着丝粒特性以了解 染色质和基因组对着丝粒功能的贡献。

项目成果

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

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

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