Mechanism of Poly-ADP-ribose function in the spindle

纺锤体中聚-ADP-核糖的功能机制

• 批准号: 6944239
• 负责人: PAUL CHANG
• 金额: $ 4.83万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6944239
• 关键词: ADP ribosylation; Xenopus; Xenopus oocyte; adenosine diphosphate; cell cycle; centrosome; chemical chain length; chemical kinetics; chemical structure function; chromatography; chromosomes; cytoskeletal proteins; enzyme substrate; genetic regulation; immunoelectron microscopy; intermolecular interaction; mass spectrometry; microtubules; mitotic spindle apparatus; polymerization; posttranslational modifications; ribose

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.

描述（由申请人提供）： 聚ADP核糖（PAR）是一种高度分支，带负电荷的核酸聚合物，可介导对DNA损伤的反应，调节转录并参与凋亡。这种功能的多样性源于其活性的两种机制。蛋白质的多ADP-核糖基化导致总体蛋白电荷的快速变化，导致蛋白质 - 蛋白质相互作用改变，而PAR作为结构基质的功能，由于非共价相互作用而隔离了核蛋白。聚ADP核糖化的程度和PAR的总量受聚合酶（PARP）活性的平衡来调节，这会催化ADP核糖从NAD转移到受体蛋白上，以及聚合物蛋白质的水解蛋白质和免费的蛋白质。虽然PARP是最称为核蛋白的，但五个鉴定出的PARP中的三个定位于有丝分裂纺锤体，表明PAR可能对主轴功能很重要。初步实验证明了对主轴函数的PAR的要求。在这里，我建议检查PAR在有丝分裂纺锤体中起作用的机制。