The Function of Werner Syndrome Protein

维尔纳综合征蛋白的功能

• 批准号: 10471686
• 负责人: Vilhelm A Bohr
• 金额: $ 66.92万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10471686
• 关键词: ATP phosphohydrolase; Affect; Aging; Amino Acids; Biochemical; Cell Cycle Regulation; Cells; Confocal Microscopy; Coupled; DNA; DNA Damage; DNA Repair; DNA metabolism; Defect; Disease; Epigenetic Process; Exonuclease; Genetic Recombination; Genomic Instability; Individual; Investigation; Laboratories; Lead; Life; Malignant Neoplasms; Mutate; Mutation; Pathway interactions; Patients; Post-Translational Protein Processing; Premature aging syndrome; Process; Proteins; Risk; Signs and Symptoms; Site; Site-Directed Mutagenesis; Time; Tissues; WRN gene; Werner Syndrome; epigenome; experience; helicase; insight; loss of function; normal aging; senescence

Patients with mutations in the WRN gene develop Werner syndrome (WS), a premature aging disorder. In general, WS cells have a high level of genomic instability, with increased amounts of DNA deletions, insertions, and rearrangements. These effects could potentially be the result of defects in DNA repair, replication, and/or recombination, although the actual biochemical defect remains unclear. In addition to being a premature aging disorder, WS patients develop a unique set of cancers and therefore studying WS affords us an opportunity to investigate the relationship between cancer and aging. Notably, aging is the greatest risk fact for cancer and involves senescence and the loss of function of tissues. We, and others, have shown that loss of Wrn impacts the epigenome and epigenetic changes are common in aging. How WRN protein contributes to cancer and aging in various tissues is under investigation. WRN protein possesses both helicase and exonuclease functions. Our laboratory investigates the localization of WRN to sites of DNA damage using confocal microscopy coupled with site directed mutagenesis of critical amino acids in WRN protein. Our findings show that basic residues are important for its localization and that amino acids modified by posttranslational modifications can modulate WRNs re-localization to sites of DNA and its retention times there.

WRN基因突变的患者会患上沃纳综合征（WS），这是一种过早衰老的疾病。一般来说，WS细胞具有高水平的基因组不稳定性，DNA缺失、插入和重排的量增加。这些影响可能是DNA修复、复制和/或重组缺陷的结果，尽管实际的生化缺陷仍不清楚。 除了是一种过早衰老的疾病外，WS患者还患上了一系列独特的癌症，因此研究WS为我们提供了一个研究癌症与衰老之间关系的机会。值得注意的是，衰老是癌症的最大风险事实，涉及衰老和组织功能的丧失。我们和其他人已经表明，Escherichia coli蛋白的丢失会影响表观基因组，表观遗传变化在衰老中很常见。WRN蛋白如何在各种组织中促进癌症和衰老正在研究中。 WRN蛋白同时具有解旋酶和核酸外切酶的功能。我们的实验室调查的WRN的本地化的网站的DNA损伤，使用共聚焦显微镜加上WRN蛋白质中的关键氨基酸的定点突变。我们的研究结果表明，碱性残基是重要的，其本地化和翻译后修饰修饰的氨基酸可以调节WRN重新定位到DNA的网站和它的保留时间。