DNA double-strand break repair, chromosomes translocations and cancer

描述(申请人提供)：DNA双链断裂(DSB)修复防止持续的DNA损伤，抵消基因组的不稳定和抑制肿瘤的发展。然而，DSB修复也有可能产生致癌的染色体易位和重排。这一高度整合的程序将阐明DSB修复启动的机制和调控，以及它对淋巴瘤和乳腺癌模型中DSB修复选择、染色体易位和肿瘤发展的影响。特别是，该计划将调查微同源介导的末端连接(MMEJ)的调节，这是一种DSB修复的致病形式，负责很大一部分致癌染色体易位。所有以DNA处理和CtIP为重点的项目的初步研究都产生了一个有重点和有凝聚力的计划。赛明顿博士将使用基因分析来评估DNA切除对MMEJ的影响，并调查MMEJ与其他DSB修复模式之间的竞争。赛明顿博士还将在哺乳动物细胞中开发灵敏的物理切除分析，这是目前明显缺乏的一项技术。Gautier博士和Gottesman博士将研究在参与MMEJ的中间体DSB中产生持续的、短的单链DNA悬垂的机制(S)。他们的研究将集中在CtIP的作用上，CtIP是一种参与DNA切除启动的蛋白质。在第三个项目中，查博士和达拉-法维拉将评估这一角色 CtIP在淋巴细胞发育和恶性转化过程中对程序性DSB的修复作用。他们还将测试这一假设，即CtIP至少部分地介导了c-Myc的致癌功能，包括其在基因组不稳定中的未确定角色。贝尔博士将确定CtIP如何促进P53基因缺陷小鼠的乳腺癌发展，并将测试CtIP缺失是否也能抑制BRCA1基因缺陷小鼠的基底样乳腺癌。最后，他将评估CtIP在Myc驱动的乳腺肿瘤发展中的潜在作用。为了实现这些目标，这些项目将广泛依赖三个相互关联的核心：管理、基因组不稳定性的分子分析和病理学。该项目和核心领导人在基因组稳定性及其在癌症中丢失的机制方面有着非常强大的合作历史、在培训方面的共同努力和共同利益。

DESCRIPTION (provided by applicant): DNA double-strand break (DSB) repair prevents persistent DNA damage, counteracts genome instability and suppresses tumor development. However, DSB repair also has the potential to produce oncogenic chromosome translocations and rearrangements. This highly integrated program will elucidate the mechanism and regulation of DSB repair initiation and its impact on DSB repair choice, chromosome translocation and cancer development in model of lymphoma and breast cancer. In particular, the program will investigate the regulation of microhomology-mediated end-joining (MMEJ), a pathogenic form of DSB repair responsible for a significant fraction of tumorigenic chromosome translocations. Preliminary studies from all projects focusing on DNA processing and CtIP have generated a focused and cohesive program. Dr. Symington will use genetic analysis to assess how DNA resection affects MMEJ and to investigate the competition between MMEJ and other modes of DSB repair. Dr. Symington will also develop sensitive physical resection assays in mammalian cells, a technology which is notably lacking at present. Drs. Gautier and Gottesman will study the mechanism(s) that generate persistent, short ssDNA overhangs at DSBs, an intermediate involved in MMEJ. Their studies will focus on the role of CtIP, a protein involved in initiation of DNA resection. In the third project, Drs. Zha and Dalla-Favera will evaluate the role of CtIP in repair of programmed DSBs during lymphocyte development and malignancy. They will also test the hypothesis that CtIP mediates, at least in part, the oncogenic function of c-Myc including its undefined role in genomic instability. Dr. Baer, will determine how CtIP facilitates breast tumor development in p53-deficient mice and will test whether CtIP loss can also suppress basal-like breast cancer in BRCA1-deficient mice. Finally, he will evaluate the potential role of CtIP in Myc-driven breast tumor development. To accomplish these goals, the projects will rely extensively on three interlinked cores: administrative, molecular analysis of genomic instability and pathology. The project and core leaders have a very strong history of collaboration, joint efforts in training and common interests in genome stability and the mechanisms of its loss in cancer.