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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

基本信息

批准号：
7195966
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
项目类别：
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/7195966
关键词：
Acute Promyelocytic Leukemia Affect Aneuploidy Apoptosis Apoptosis Regulation Pathway Applications Grants Base Excision Repairs Binding Blast Cell CDKN1A gene Caspase Cell Aging Cell Count Cell Cycle Cell Cycle Deregulation Cell Cycle Progression Cell Death Cell Line Cell physiology Cells Centrosome Ceramides Chemicals Chimeric Proteins Chromosomal translocation Chromosome Segregation Chromosomes DNA Damage DNA Repair DNA biosynthesis Development Disease remission Disruption Embryo Ensure Enzymes Excision Repair Fibroblasts Gene Targeting Genes Genome Stability Genomic Instability Grant H2AFX gene Human Incidence Interferons Investigation Knockout Mice Knowledge Laboratories Light Localized Mitosis Monitor Movement Mus Myelogenous Nonhomologous DNA End Joining Normal Cell Nuclear Nuclear Protein Nuclear Proteins Numbers Oncogenes Oncogenic PML gene Pathogenesis Pathway interactions Pattern Personal Satisfaction Phase Phosphoric Monoester Hydrolases Phosphotransferases Play Progranulocytes Protein Overexpression Proteins Rattus Regulation Regulation of Apoptosis Pathway Reporting Research Personnel Retinoic Acid Receptor Role Screening procedure Site Splenocyte Syndrome Telomere Pathway Testing Transcriptional Activation Transgenic Animals Transgenic Mice Translational Regulation Tretinoin Tumor Necrosis Factor-alpha Tumor Necrosis Factors Tumor Suppressor Proteins Tumorigenicity Yeasts aurora-A kinase base bone carcinogenesis cell growth design granulocyte homologous recombination human H2AX protein human TNF protein in vivo interest leukemia monocyte novel oncoprotein p21 prevent programs protein B repaired research study response t(15 17)(q22 q12)transcription factor tumor tumor growth yeast two hybrid system

项目摘要

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(申请人提供)：肿瘤抑制基因PML在多种细胞功能中发挥重要作用。过去10年在APL领域的研究积累了足够的信息，最终证明PML-RARA融合蛋白与急性早幼粒细胞白血病(APL)的发病机制有关。在接下来的5年里，我们将根据我们最近的几项发现，将这笔赠款的主要目标重新定位为PML在基因组稳定性和DNA损伤反应中的作用。我们实验室最近报道了PML3在中心体复制和基因组稳定性中的重要作用。特异性敲除PML3导致中心体扩增，支持PML3在维持中心体完整性中的作用。我们进行了酵母双杂交筛选，并鉴定了几个有趣的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，一种新的中心体蛋白，也是中心体调节因子CDc14A的结合伙伴。我们的研究表明，PML功能在IR诱导的许多参与DNA损伤反应的酶的形成中是必不可少的。我们的主要假设是，PML在维持中心体完整性、确保有丝分裂过程中适当的染色体分离以及DNA损伤反应中发挥重要作用。本研究的具体目标如下：1.研究PML3在调节中心体功能中的作用。有待检验的假设：PML3控制中心体复制并在细胞周期进程中维持适当数量的中心体，PML3功能的丧失会导致中心体扩增、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。有待检验的假设：PML3特异的相互作用蛋白对于中心体功能和维持基因组稳定性是重要的。3.探讨PML在DNA损伤反应中的作用。有待验证的假说：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。鉴于最近有报道称，在不同来源的人类原发肿瘤中发现PML缺乏症的发生率很高，了解PML在基因组稳定性和DNA损伤反应中的功能作用将为我们进一步了解目前的癌症发生机制提供有价值的信息。