A Role for PML in Genome Stability and DNA Damage Response

PML 在基因组稳定性和 DNA 损伤反应中的作用

• 批准号: 7373528
• 负责人: KUN-SANG CHANG
• 金额: $ 26.41万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7373528
• 关键词: Acute Promyelocytic Leukemia; Affect; Aneuploidy; Apoptosis Regulation Pathway; Applications Grants; Base Excision Repairs; Binding; Cell Aging; Cell Cycle Progression; Cell physiology; Cells; Centrosome; Chimeric Proteins; Chromosome Segregation; Chromosomes; DNA Damage; DNA Repair; DNA biosynthesis; Development; Ensure; Enzymes; Excision Repair; Genome Stability; Genomic Instability; Grant; H2AFX gene; Human; Incidence; Investigation; Knowledge; Laboratories; Light; Localized; Mitosis; Monitor; Movement; Nonhomologous DNA End Joining; Numbers; Pathogenesis; Phosphoric Monoester Hydrolases; Phosphotransferases; Play; Protein Overexpression; Proteins; Regulation; Regulation of Apoptosis Pathway; Reporting; Research Personnel; Role; Screening procedure; Site; Telomere Pathway; Testing; Translational Regulation; Tumor Suppressor Proteins; Yeasts; aurora-A kinase; base; carcinogenesis; design; homologous recombination; human H2AX protein; in vivo; interest; novel; prevent; programs; protein B; repaired; research study; response; transcription factor; tumor; yeast two hybrid system

DESCRIPTION (provided by applicant): The tumor suppressor PML plays essential roles in multiple cellular functions. Investigations accomplished in the APL field over the past 10 years have accumulated sufficient information to conclusively demonstrate that PML-RARA fusion protein is responsible for the pathogenesis of acute promyelocytic leukemia (APL). Over the next 5 years we will redirect the major objectives of this grant to focus on PML's role in genome stability and DNA damage response based on several of our recent findings. Our laboratory recently reported an important role for PML3 in centrosome duplication and genome stability. Specific knockdown PML3 causes centrosome amplification supporting a role of PML3 in maintaining centrosome integrity. We performed yeast two-hybrid screening and have identified several interesting PML3-specific interacting proteins. Specially PNK, a kinase/phosphatase essential for DNA repair by base-excision repair (BER) and non-homologous end joining (NHEJ); UXT, a novel centrosomal protein and a binding partner of the centrosome regulator Cdc14A. Our study showed that PML functions are indispensable for the formation of IR-induced foci of many enzymes involve in DNA-damage response. Our main hypothesis is that PML plays important roles in maintaining centrosome integrity to ensure proper chromosome segregation during mitosis, and in DNA damage response. The following specific aims will be pursued: 1. To investigate a role for PML3 in regulating centrosome functions. Hypothesis to be tested: PML3 controls centrosome duplication and maintains an appropriate number of centrosome during cell cycle progression, loss of PML3 function leads to centorosme amplification, chromosome missegregation, aneuploidy, and genome instability. 2. To understand the functional significance of PML3-specific interacting proteins. Hypothesis to be tested: PML3- specific interacting proteins are important for centrosome functions and maintaining genome stability. 3. To investigate a role for PML in DNA damage response. Hypothesis to be tested: PML plays important role in DNA damage response by regulating the enzymes involved in DNA-damage repair and DNA replication. In light of the recent report that a high incidence of a PML-deficiency was found in a diverse origin of primary human tumors, understanding the functional roles of PML in genome stability and DNA damage response will provide valuable information to further our current knowledge in carcinogenesis.

描述（由申请人提供）：肿瘤抑制因子 PML 在多种细胞功能中发挥重要作用。过去10年在APL领域完成的研究已经积累了足够的信息，最终证明PML-RARA融合蛋白是急性早幼粒细胞白血病(APL)的发病机制。在接下来的 5 年里，我们将根据我们最近的一些发现，重新调整这笔资助的主要目标，重点关注 PML 在基因组稳定性和 DNA 损伤反应中的作用。我们的实验室最近报道了 PML3 在中心体复制和基因组稳定性中的重要作用。特异性敲低 PML3 会导致中心体扩增，支持 PML3 在维持中心体完整性方面的作用。我们进行了酵母双杂交筛选，并鉴定了几种有趣的 PML3 特异性相互作用蛋白。特别是 PNK，一种通过碱基切除修复 (BER) 和非同源末端连接 (NHEJ) 进行 DNA 修复所必需的激酶/磷酸酶； UXT，一种新型中心体蛋白，是中心体调节因子 Cdc14A 的结合伴侣。我们的研究表明，PML 功能对于许多参与 DNA 损伤反应的酶的 IR 诱导灶的形成是不可或缺的。我们的主要假设是 PML 在维持中心体完整性以确保有丝分裂期间染色体正确分离以及 DNA 损伤反应中发挥着重要作用。我们将追求以下具体目标： 1. 研究 PML3 在调节中心体功能中的作用。待检验的假设：PML3在细胞周期进程中控制中心体复制并维持适当数量的中心体，PML3功能的丧失导致中心体扩增、染色体错误分离、非整倍体和基因组不稳定。 2. 了解PML3特异性相互作用蛋白的功能意义。待检验的假设：PML3 特异性相互作用蛋白对于中心体功能和维持基因组稳定性很重要。 3. 探讨PML在DNA损伤反应中的作用。待检验的假设：PML 通过调节参与 DNA 损伤修复和 DNA 复制的酶，在 DNA 损伤反应中发挥重要作用。鉴于最近的报告称，在原发性人类肿瘤的不同起源中发现了 PML 缺陷的高发生率，了解 PML 在基因组稳定性和 DNA 损伤反应中的功能作用将为进一步加深我们目前对癌症发生的了解提供有价值的信息。