Function of Human Damaged DNA Binding Protein (DDB)

人类受损 DNA 结合蛋白 (DDB) 的功能

• 批准号: 7070030
• 负责人: STUART M LINN
• 金额: $ 35.31万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7070030
• 关键词: DNA binding protein; DNA damage; DNA directed DNA polymerase; DNA repair; RNA interference; Schizosaccharomyces pombe; cell transformation; gene mutation; gene targeting; genetic promoter element; genetic transcription; genetically modified animals; human genetic material tag; immunofluorescence technique; immunoprecipitation; laboratory mouse; matrix assisted laser desorption ionization; nucleic acid sequence; polymerase chain reaction; protein protein interaction; protein structure function; radiobiology; western blottings; yeast two hybrid system

DESCRIPTION (provided by applicant): DDB is a mammalian heterodimer of p127 (DDB1) and p48 (DDB2). It binds to DNA damages and interacts with a number of protein complexes, including E2F1, p300, STAGA and DNA polymerase epsilon, as well as with transactivator proteins of transforming viruses, including HB virus protein X and EB virus EBNA 2. Mutations in DDB2 give rise to xeroderma pigmentosum group E. No naturally occurring human mutations of DDB1 are known. It is likely that DDB1 and DDB2 have individual functions beyond the DDB heterodimeric DNA damage binding. The long-term goals of this project are to understand the role(s) of DDB, especially as a cancer antagonist. During the coming period it is proposed to characterize and study the DDB2 (-/-) and (-/+) mice just obtained in the laboratory and cells derived from them. Gene disruptions of DDB1 with RNAi in human cells will also be explored as will a deletion mutant of the DDB1 homologue of the fission yeast, S. pombe that was also just isolated in the laboratory. The laboratory recently showed that XP-E cells are actually abnormally resistant to UV radiation as they produce little or no p53 constitutively or in response to UV irradiation and hence do not undergo p53-mediated apoptosis. These phenomena will be further studied. Finally, a recent observation that DDB interacts with DNA polymerase epsilon will be further studied. Together these studies will help us to understand the genesis of cancers after UV irradiation, especially in xeroderma pigmentosum, as well as how viral infection can lead to cellular transformations.

描述（由申请人提供）： DDB是P127（DDB1）和P48（DDB2）的哺乳动物异二聚体。 It binds to DNA damages and interacts with a number of protein complexes, including E2F1, p300, STAGA and DNA polymerase epsilon, as well as with transactivator proteins of transforming viruses, including HB virus protein X and EB virus EBNA 2. Mutations in DDB2 give rise to xeroderma pigmentosum group E. No naturally occurring human mutations of DDB1 are known. DDB1和DDB2很可能具有超出DDB异二聚体DNA损伤结合的个体功能。该项目的长期目标是了解DDB的作用，尤其是作为癌症拮抗剂。在接下来的一段时间内，提议表征和研究刚刚在实验室中获得的DDB2（ - / - ）和（ - /+）小鼠。还将探索DDB1在人类细胞中与RNAi的基因破坏，也将被探索，因为裂变酵母菌的DDB1同源物的缺失突变体也将被探索，该突变体也只是在实验室中分离出来的。该实验室最近表明，XP-E细胞实际上对紫外线辐射具有异常抗性，因为它们几乎没有或没有组成p53或响应紫外线照射，因此不经历p53介导的细胞凋亡。这些现象将进一步研究。最后，将进一步研究DDB与DNA聚合酶Epsilon相互作用的最近观察结果。这些研究将共同​​帮助我们了解紫外线照射后的癌症的起源，尤其是在心胚层色素中，以及病毒感染如何导致细胞转化。