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.
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