Mechanism of Poly-ADP-ribose function in the spindle

描述(由申请人提供)： 聚腺苷二磷酸核糖(PAR)是一种高度支化的、带负电荷的核酸聚合物，它介导对DNA损伤的反应，调节转录，并参与细胞凋亡。这种功能的多样性源于它的两种活性机制：蛋白质的多聚ADP-核糖化导致蛋白质总电荷的快速而戏剧性的变化，从而导致蛋白质-蛋白质相互作用的改变，以及PAR作为结构基质的功能，由于非共价电荷相互作用，核蛋白被隔离在其上。多聚ADP核糖化的程度和PAR的总量受PAR聚合酶(PARP)活性和多ADP核糖水解酶(PARG)活性的平衡调节，PARP活性催化ADP核糖从NAD转移到受体蛋白上，PARG活性水解PAR聚合物并将其从受体蛋白中释放出来。虽然PAR最为人所知的是核蛋白，但已鉴定的五个PAP中有三个定位于有丝分裂的纺锤体，这表明PAR可能对纺锤体的功能很重要。初步实验证明，主轴功能对PAR的要求很高。在这里，我建议研究PAR在有丝分裂纺锤体中的作用机制。

DESCRIPTION (provided by applicant): Poly ADP ribose (PAR) is a highly branched, negatively charged nucleic acid polymer which mediates the response to DNA damage, regulates transcription, and is involved in apoptosis. This diversity of function stems from its two mechanisms of activity; poly-ADP-ribosylation of proteins leads to a rapid and dramatic change in overall protein charge resulting in altered protein-protein interactions, and PAR functions as a structural matrix onto which nuclear proteins are sequestered due to non-covalent charge interactions. The extent of poly ADP ribosylation and the total amount of PAR are regulated by the balance of PAR polymerase (PARP) activity, which catalyze the transfer of ADP ribose from NAD onto acceptor proteins, and poly-ADP ribose glycohydrolase (PARG) activity, which hydrolyses the PAR polymer and frees it from the acceptor protein. While PARPs are best known as nuclear proteins, three of five identified PARPs localize to the mitotic spindle suggesting PAR may be important for spindle function. Preliminary experiments demonstrate a requirement for PAR in spindle function. Here, I propose to examine the mechanism by which PAR acts in the mitotic spindle.