San is a putative acetyltransferase that is essential for viability and sister chromatid cohesion in Drosophila, but its homologue is completely dispensable in budding yeast. This raises the question whether the cohesion function of San is conserved. We found that, in HeLa cells, both San and its enzymatic activity are required for sister chromatid cohesion, specifically at the centromeres but not chromosome arms. This indicates that San is required for a cohesion mechanism that is conserved only in metazoans. The study of a metazoan- specific factor is critical for the understanding of sister chromatid cohesion in higher eukaryotes, which is poorly understood and notably different from that in yeast. In terms of medical applications, chromosome instability strongly associates with cancers. Moreover, cohesion molecules have been implicated in genetic disorders, such as Roberts Syndrome and Cornelia de Lange Syndrome. The following studies will contribute to basic science research and could lead to important medical applications. The short-term objective is to understand how San mediates sister chromatid cohesion. Although not modifying any of the known cohesion factors in vitro, San acetylates many chromosome-associated proteins. Identification of the substrates is critical for revealing the downstream mechanisms. Regarding the upstream regulation, San localizes to the cytoplasm in interphase cells and its activity is regulated by an inhibitory mechanism. This proposal will build on the above findings and focus on the role of San in sister chromatid cohesion, specifically the downstream substrates and upstream regulation. The long-term objective is to build a comprehensive understanding of the functions of San. San acetylates many substrates. It is highly possible that some substrates are involved in functions different from sister chromatid cohesion. The proposed study will provide entry points for additional functions of San. In addition, San may be used as a drug target for cancer therapy. Identification of small molecules that modulate the San mechanism may provide practical medical applications.
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