Modulation of DNA Repair by the Protein Component of Chromatin

染色质蛋白质成分对 DNA 修复的调节

• 批准号: 1817417
• 负责人: Sarah Delaney
• 金额: $ 75万
• 依托单位: Brown University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1817417&HistoricalAwards=false
• 关键词: Modulation; DNA; Repair; Protein; Component

The DNA in cells is constantly exposed to reactive molecules that can chemically alter bits of the DNA. Because DNA serves as the source of genetic information for cellular life, cells have devised sophisticated methods for repairing damaged DNA. Effective repair is necessary for cellular survival and transfer of error-free genetic material to the next generation. Despite the importance of DNA repair, there is still much we do not understand about the process. A focus in this project is to study how DNA repair is influenced by the type of DNA packaging that occurs in the nucleus, whereby strands of DNA are wound around cylindrical protein cores, like thread around a spool. By assembling damage-containing DNA wrapped around protein cores in the laboratory, researchers will apply cutting-edge methods to study how DNA packaging affects the ability of cells to replace damaged segments in DNA with new ones. The research will be carried out by graduate and undergraduate research as part of their professional training for careers in STEM. Collaborations with two female faculty and their students at colleges for women will expand the broader research opportunities. Oxidation, alkylation, and deamination of DNA bases can cause mutations and halt replication; therefore, to maintain genomic stability, this kind of damage must be repaired. Base excision repair (BER) is a coordinated series of enzyme-catalyzed chemical reactions in which the damaged base is removed and replaced. Despite our significant knowledge of BER, much of what has been learned is based on repair of damage in DNA templates devoid of the chromatin proteins that package DNA in the nucleus. This project focuses on the ability of the protein component of chromatin, the histones, to modulate initiation of BER. Using biochemical methodologies and kinetics techniques, the research will provide a comprehensive description of the ability of histones to govern DNA repair in the compacted environment of chromatin. The specific goals of the research are (i) to determine the ability of variants of the histone proteins to regulate BER, (ii) to understand how post-translational modification of histones influences BER, and (iii) to establish the contribution of the terminal regions of the histones to their overall activity. The results are expected to provide a deeper understanding of how BER occurs in the nuclear context.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

细胞中的DNA不断暴露于反应分子，这些分子可以化学改变DNA的片段。由于DNA是细胞生命的遗传信息来源，细胞已经设计出复杂的方法来修复受损的DNA。 有效的修复对于细胞存活和将无错误的遗传物质转移到下一代是必要的。 尽管DNA修复的重要性，我们仍然有很多不了解的过程。该项目的一个重点是研究DNA修复如何受到细胞核中发生的DNA包装类型的影响，DNA链缠绕在圆柱形蛋白质核心上，就像线轴上的线一样。 通过在实验室中组装包裹在蛋白质核心周围的含有损伤的DNA，研究人员将应用尖端方法来研究DNA包装如何影响细胞用新DNA替换DNA中受损片段的能力。该研究将由研究生和本科生进行研究，作为他们在STEM职业生涯的专业培训的一部分。与两名女教师和她们在女子学院的学生合作将扩大更广泛的研究机会。DNA碱基的氧化、烷基化和脱氨作用会导致突变并停止复制;因此，为了保持基因组的稳定性，必须修复这种损伤。 碱基切除修复（BER）是一系列酶催化的化学反应，其中受损的碱基被移除和替换。尽管我们对BER有着丰富的知识，但我们所学到的大部分知识都是基于DNA模板中的损伤修复，而DNA模板中缺乏在细胞核中包装DNA的染色质蛋白。 这个项目的重点是染色质的蛋白质组分，组蛋白，以调节BER的启动能力。使用生物化学方法和动力学技术，该研究将提供组蛋白在染色质致密环境中管理DNA修复的能力的全面描述。该研究的具体目标是（i）确定组蛋白变体调节BER的能力，（ii）了解组蛋白的翻译后修饰如何影响BER，以及（iii）确定组蛋白末端区域对其整体活性的贡献。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的知识价值和更广泛的影响审查标准进行评估来支持。

项目成果

Nucleosome Core Particles Lacking H2B or H3 Tails Are Altered Structurally and Have Differential Base Excision Repair Fingerprints

• DOI: 10.1021/acs.biochem.0c00877
• 发表时间: 2021-01-10
• 期刊: BIOCHEMISTRY
• 影响因子: 2.9
• 作者: Caffrey, Paul J.;Delaney, Sarah
• 通讯作者: Delaney, Sarah

Initiating base excision repair in chromatin.

• DOI: 10.1016/j.dnarep.2018.08.011
• 发表时间: 2018-11
• 期刊: DNA repair
• 影响因子: 3.8
• 作者: Kennedy EE;Caffrey PJ;Delaney S
• 通讯作者: Delaney S

Global Repair Profile of Human Alkyladenine DNA Glycosylase on Nucleosomes Reveals DNA Packaging Effects

• DOI: 10.1021/acschembio.9b00263
• 发表时间: 2019-08-01
• 期刊: ACS CHEMICAL BIOLOGY
• 影响因子: 4
• 作者: Kennedy, Erin E.;Li, Chuxuan;Delaney, Sarah
• 通讯作者: Delaney, Sarah

Nucleosomes and the three glycosylases: High, medium, and low levels of excision by the uracil DNA glycosylase superfamily.

• DOI: 10.1016/j.dnarep.2018.09.008
• 发表时间: 2018-12
• 期刊: DNA repair
• 影响因子: 3.8
• 作者: Tarantino ME;Dow BJ;Drohat AC;Delaney S
• 通讯作者: Delaney S

Histone H2A Variants Enhance the Initiation of Base Excision Repair in Nucleosomes

• DOI: 10.1021/acschembio.9b00229
• 发表时间: 2019-05-01
• 期刊: ACS CHEMICAL BIOLOGY
• 影响因子: 4
• 作者: Li, Chuxuan;Delaney, Sarah
• 通讯作者: Delaney, Sarah