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Hydroxymethylcytosine Stabilizes Holliday Junctions and Promotes Recombination via Interaction with Endonuclease G

羟甲基胞嘧啶通过与核酸内切酶 G 相互作用稳定霍利迪连接并促进重组

基本信息

批准号：
8991661
负责人：
Crystal Marie Vander Zanden
金额：
$ 3.4万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8991661
关键词：
Address Affect Affinity Amines Binding Biochemistry Cancerous Cell physiology Cells Cleaved cell Collaborations Cruciform DNA Crystallography Cytosine DNA DNA Repair DNA Sequencing Facility DNA Structure Differential Scanning Calorimetry Disease Double Strand Break Repair Electrophoretic Mobility Shift Assay Enzymes Epigenetic Process Gene Expression Genetic Markers Genetic Recombination Genome Genomics Goals Human Genome Hydrogen Bonding Information Sciences Knowledge Learning Link Literature Malignant Neoplasms Measures Metabolism Methods Modeling Molecular Conformation Oxygen Play Positioning Attribute Process Proteins Recording of previous events Recruitment Activity Regulation Research Role Scientist Series Site Structure Techniques Testing Thermodynamics Vertebral column Work X-Ray Crystallography base cancer cell cell type endonuclease G epigenetic marker experience inorganic phosphate interest knowledge base mammalian genome prevent public health relevance repaired

项目摘要

DESCRIPTION (provided by applicant): Epigenetic modifiers play vital roles in directing DNA structure, regulating gene expression, and determining disease-states. Scientists have recently taken interest in a epigenetic marker, 5-hydroxymethylcytosine (5hmC), which represents less than one percent of cytosines in the mammalian genome. Initially, 5hmC was thought primarily to be an intermediate in methylcytosine metabolism, but now the field is beginning to recognize 5hmC's involvement in a variety of cellular functions, even calling it the "sixth base" of the genome. One observation is that high local genomic concentrations of 5hmC have been linked to DNA recombination. Furthermore, the recombination protein Endonuclease G (Endo G) has been recently found to preferentially cleave 5hmC modified DNA over unmodified DNA. The proposed research aims to explore this link between 5hmC, Endo G, and recombination. The hypothesis is that 5hmC-modified DNA forms unique hydrogen bonds that promote pausing of a migrating DNA Holliday junction, and the paused junction provides a stable substrate for Endo G to bind. This model will be explored from a structural perspective with two specific aims. The first aim is to determine the structure and thermodynamics of 5hmC DNA using x-ray crystallography and differential scanning calorimetry. The second aim is to define the role of 5hmC on Endo G recognition by testing the binding of Endo G to a series of 5hmC, 5methyl-C, and unmodified-C duplex and junction DNA constructs. Overall, the mechanisms behind recombination aren't fully understood, and 5hmC is likely an important part the regulation process. Since recombination is an integral part of the DNA damage repair mechanism, 5hmC may help to target local DNA regions for repair. Particular cell types, including cancer cells, express lower levels of 5hmC. This suggests 5hmC levels are linked to the disease-state of cancer cells by de-regulating their DNA repair. This research will help build the fundamental base of knowledge for understanding recombination-related diseases. A complete understanding of 5hmC will furthermore help decode the mechanisms of genomic regulation, impacting more than just the recombination field.

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Force Field Model of Periodic Trends in Biomolecular Halogen Bonds.

DOI：
10.1021/jp509003r
发表时间：
2015-07-23
期刊：
The journal of physical chemistry. B
影响因子：
0
作者：
Scholfield MR;Ford MC;Vander Zanden CM;Billman MM;Ho PS;Rappé AK
通讯作者：
Rappé AK

Structural adaptation of vertebrate endonuclease G for 5-hydroxymethylcytosine recognition and function

DOI：
10.1093/nar/gkaa117
发表时间：
2020-02
期刊：
Nucleic Acids Research
影响因子：
14.9
作者：
Crystal M Vander Zanden-Crystal-M-Vander Zanden-2127635681;R. S. Czarny;Ethan N Ho;A. Robertson;P. S. Ho
通讯作者：
Crystal M Vander Zanden-Crystal-M-Vander Zanden-2127635681;R. S. Czarny;Ethan N Ho;A. Robertson;P. S. Ho

Effect of Hydroxymethylcytosine on the Structure and Stability of Holliday Junctions.

羟基胞霉素对霍利迪连接结构和稳定性的影响。