Elucidating the role of mai1 in cell cycle control and DNA damage response

描述（由申请人提供）：细胞通过激活导致细胞周期停滞、DNA修复和细胞凋亡的信号转导途径对DNA损伤作出反应。DNA损伤检查点对于维持基因组的完整性是必不可少的。DNA损伤反应在人类病理学，特别是癌症中的重要性已得到充分证实。编码DNA损伤检查点蛋白的各种基因中的突变与各种人类疾病综合征相关，并且这些疾病综合征通常以增加的癌症易感性为特征。虽然在理解DNA损伤检查点方面已经取得了重大进展，但构成DNA损伤反应的途径网络是复杂的，其他组分仍有待确定。我们已经筛选了突变斑马鱼胚胎的DNA损伤反应缺陷。这确定了两个突变株系，暴露于电离辐射后不能阻止有丝分裂进入。这些细胞系中的每一条都携带着一个我们称之为mail的基因突变（辐射后的有丝分裂1）。mail基因编码的蛋白质与其他脊椎动物物种（包括人类）的直系同源物。在这些物种中存在高度保守的氨基酸块，但没有基序或结构域表明潜在的生物学功能。除了检查点表型之外，未经辐照的邮件斑马鱼在正常细胞周期进程中存在缺陷。该提案的目标是确定邮件在细胞周期调节和DNA损伤检查点中的作用。有两个具体目标：（1）研究Mail斑马鱼突变体的DNA损伤检查点和细胞周期缺陷;（2）建立Mail在人类细胞中的功能。

DESCRIPTION (provided by applicant): Cells respond to DNA damage by activating signal transduction pathways that lead to cell cycle arrest, DNA repair and apoptosis. DNA damage checkpoints are essential for the maintenance of genomic integrity. The importance of the DNA damage response in human pathology, especially cancer, is well established. Mutations in various genes encoding DNA damage checkpoint proteins are associated with a variety of human disease syndromes and these are often characterized by an increased predisposition to cancer. Although significant progress has been made understanding DNA damage checkpoints, the network of pathways that compose the DNA damage response is complex and additional components remain to be identified. We have screened mutant zebrafish embryos for DNA damage response defects. This identified two mutant lines that fail to arrest mitotic entry following exposure to ionizing radiation. Each of these lines carries a mutation in a gene that we have named mail (mitosis after irradiation 1). The mail gene encodes a protein with orthologues in other vertebrate species, including humans. There are blocks of amino acids that are highly conserved across these species, but no motifs or domains to suggest a potential biological function. In addition to a checkpoint phenotype, unirradiated mail zebrafish have a defect in normal cell cycle progression. The goal of this proposal is to determine Mail's role in cell cycle regulation and DNA damage checkpoints. There are two specific aims: (1) to investigate the DNA damage checkpoint and cell cycle defects of mail zebrafish mutants; and (2) to establish the function of Mail in human cells.