Research Project
9516370
Program Director/Principal Investigator (Last, First, Middle): Song, Mi Hye Summary The centrosome is the primary microtubule-organizing center in animal cells, and is vital for the maintenance of genomic integrity. For the fidelity of cell division, the centrosome must duplicate only once per cell cycle, and duplicated centrosomes establish bipolar spindles that are crucial for accurate chromosome segregation. Aberrant centrosomes are often associated with many human disorders including cancers and microcephaly, where extra centrosomes lead to chromosome segregation errors and abnormal cell proliferation leading to genomic instability and defective brain development. Our long-term goal is to elucidate the molecular mechanisms of centrosome assembly and function using the C. elegans embryo as an in vivo model. The overall objective is to understand how the anaphase promoting complex/cyclosome (APC/C) and a cofactor FZR-1 (a homolog of human Cdh1) regulates centrosome assembly by proteolysis. The APC/C complex is an E3 ubiquitin ligase that ubiquitinates its substrates for proteasomal destruction. FZR-1/Cdh1 is an APC/C cofactor that confers a specific substrate-binding through recognition of conserved motifs. Cdh1-deficient mouse exhibits embryonic lethality and genomic instability. In animal cells, proper levels of centrosome proteins are critical for the correct number of centrosomes, which is regulated by the timely proteolysis. While we realize the great impact of the APC/C complex for proper cell division, we understand little about how the APC/C-mediated proteolysis contributes to normal centrosome assembly. Our hypothesis is that the APC/CFZR-1 targets a key centrosome factor(s) and other effectors to orchestrate proper levels and subcellular localization in a cell cycle dependent manner. Identifying specific substrates of the APC/CFZR-1 in centrosome assembly and defining the role will reveal the mechanisms of the APC/CFZR-1 in centrosome regulation required for the fidelity of cell division. The aims of the project are to (1) determine a specific substrate(s) of the APC/CFZR-1 that compensates for impaired ZYG-1 function in centrosome assembly, (2) characterize how the APC/CFZR-1-mediated proteolysis of a specific substrate influences centrosome assembly, and (3) to identify new substrates of the APC/CFZR-1 involved in centrosome regulation. Successful completion of these aims will reveal fundamental mechanisms underlying centrosome assembly and function, an important cellular process for faithful cell division. These studies are relevant to the diagnosis and treatment of the large spectrum of human cancers and microcephaly in addition to advancing the field of centrosome biology.
