Project 2: Characterizing the role of ATM and MSH2 in genome stability

癌细胞的突变会改变它们生长和死亡的时间。细胞通过以下途径获得这些突变 DNA损伤。正常情况下，当细胞经历dna损伤时，dna修复蛋白被招募来纠正 受损或突变的DNA。如果损伤没有得到纠正，细胞死亡途径就会激活，从而杀死 手机。然而，DNA损伤反应中可能会出现错误，导致突变的细胞存活 可能导致癌症的DNA。先天携带DNA修复相关基因突变的人 容易患上癌症，而许多不是天生携带这些突变的人会患上癌症 被发现在他们的肿瘤中获得了DNA修复基因的突变。研究细胞如何修复DNA 损伤，我们用小鼠B细胞作为模型系统。以产生识别和消除 对于病原体，B细胞的遗传程序是突变和删除抗体编码基因。B细胞 仔细协调它们的DNA损伤和DNA修复途径，以避免触发细胞死亡途径。 ATM(共济失调毛细血管扩张症突变)和MSH2(MutS同源2)是两个人必不可少的蛋白质 不同的DNA修复途径。缺乏ATM或MSH2的转基因小鼠表现出抗体缺陷 产生，并具有类似的癌症易感性与出生时带有这些DNA修复基因突变的人。 然而，同时缺乏ATM和MSH2的小鼠是不可行的(未公布的数据)。我们假设 ATM和MSH2的联合丢失导致基因组DNA损伤的积累，从而防止小鼠 发展。我们建议通过实验来描述ATM和MSH2协同工作的机制 调节基因组稳定性和实验以确定这些独特的分子途径是否可以被利用 在癌症的治疗方面。这项研究将由纽约市立大学的冯博士和乔杜里博士领导 约克和纪念斯隆-凯特琳癌症中心。Vuong博士，乔杜里博士的前实习生， 将在拟议的研究中监督CCNY学生，这将加强代表不足的人的渠道 少数族裔接受过癌症研究方面的培训。拟议研究的完成将改善 Vuong博士是一名新的研究人员，他对未来拨款申请的竞争力。

Cancer cells have mutations that alter when they will grow and die. The cells acquire these mutations through DNA damage. Normally, when a cell experiences DNA damage, DNA repair proteins are recruited to correct the damaged or mutated DNA. If the damage is not corrected, a cell death pathway is activated that kills the cell. However, mistakes in the DNA damage response can occur, resulting in the survival of cells with mutated DNA that can give rise to cancer. People who are born with mutations in genes involved in DNA repair are predisposed to developing cancer and many people not born with these mutations who develop cancer have been found to have acquired mutations in DNA repair genes in their tumors. To study how cells repair DNA damage, we use mouse B cells as a model system. To generate antibodies that recognize and eliminate pathogens, B cells are genetically programmed to mutate and delete antibody coding genes. The B cells carefully coordinate their DNA damage and DNA repair pathways to avoid triggering a cell death pathway. ATM (ataxia telangiectasia mutated) and MSH2 (MutS homologue 2) are proteins that are essential for two distinct DNA repair pathways. Mice engineered to lack either ATM or MSH2 display defects in antibody production and have a similar cancer predisposition as people born with mutations in these DNA repair genes. However, mice that lack both ATM and MSH2 are not viable (unpublished data). We hypothesize that the combined loss of ATM and MSH2 causes the accumulation of genomic DNA damage that prevents mouse development. We propose experiments to characterize the mechanism by which ATM and MSH2 cooperatively regulate genome stability and experiments to determine if these unique molecular pathways can be exploited therapeutically in cancer. The research will be led by Dr. Vuong and Dr. Chaudhuri at The City College of New York and Memorial Sloan-Kettering Cancer Center, respectively. Dr. Vuong, a former trainee of Dr. Chaudhuri, will supervise CCNY students in the proposed research, which will enhance the pipeline of underrepresented minorities trained in cancer research. The completion of the proposed research will improve the competitiveness of future grant applications from Dr. Vuong, who is a new investigator.