The Function of Werner Syndrome Protein

WRN基因突变的患者会患上沃纳综合征(WS)，这是一种早衰疾病。一般来说，WS细胞具有高度的基因组不稳定性，DNA缺失、插入和重排的数量增加。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尚不清楚。 除了是一种早衰障碍，WS患者还会发展成一组独特的癌症，因此研究WS为我们提供了一个调查癌症和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。我们和其他人已经证明，WRN的丢失影响表观基因组，表观遗传学变化在衰老中很常见。WRN蛋白如何在不同组织中参与癌症和衰老的研究正在进行中。 WRN蛋白同时具有解旋酶和核酸外切酶功能。我们的实验室使用共聚焦显微镜结合WRN蛋白中关键氨基酸的定点突变来研究WRN对DNA损伤位置的定位。我们的发现表明，碱性残基对其定位很重要，经翻译后修饰的氨基酸可以调节WRNS重新定位到DNA位点及其保留时间。

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.