DF/HCC Program Affiliation

Cancer Cell Biology

Research Abstract

Accurate chromosome segregation during cell division requires dramatic changes in chromatin structure and microtubule organization and is crucial to prevent genome instability that can contribute to cancer and cause birth defects. Our research focuses on the factors that are responsible for regulation of these changes, with emphasis on the newly described mitotic kinase haspin, and on the role of histone modifications in mitosis.
Haspin is the prototypical member of a distinctive group of serine/threonine kinases conserved in eukaryotes including yeast, plants and mammals. Depletion of haspin by RNA interference prevents human cells from completing mitosis due to premature loss of cohesion between sister chromatids and failure of metaphase chromosome alignment. Haspin phosphorylates the tail of histone H3 at threonine-3 during mitosis, suggesting that it may directly regulate chromatin behavior by modifying the “histone code”. Like other kinases, haspin is likely to have multiple substrates. Indeed, haspin localizes to centrosomes as well as the chromosomes during mitosis and is likely to target spindle components in addition to chromosome proteins. We are using a variety of approaches including RNAi, immunofluorescence microscopy, protein complex purification and in vitro kinase assays to understand the role of haspin in mitosis: its role in sister chromatid cohesion, its interplay with other mitotic kinases such as aurora B, and its possible role in cancer. We are using high-throughput screening to identify specific small molecule inhibitors of haspin as in vitro research tools and to enable validation studies of haspin as a drug target in cancer. These molecules might also find direct application as chemotherapeutic agents. In addition, we are developing in vitro peptide array methods to examine the role of histone phosphorylation in the context of the histone code.

Publications

• Dai J, Sullivan BA, Higgins JM.Regulation of mitotic chromosome cohesion by Haspin and Aurora B.Dev Cell 2006 Nov;11(5):741-50.
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• Dai J, Higgins JM.Haspin: a mitotic histone kinase required for metaphase chromosome alignment.Cell Cycle 2005 May;4(5):665-8.
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• Dai J, Sultan S, Taylor SS, Higgins JM.The kinase haspin is required for mitotic histone H3 Thr 3 phosphorylation and normal metaphase chromosome alignment.Genes Dev 2005 Feb 15;19(4):472-88.
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• Higgins JM.The Haspin gene: location in an intron of the integrin alphaE gene, associated transcription of an integrin alphaE-derived RNA and expression in diploid as well as haploid cells.Gene 2001 Apr 4;267(1):55-69.
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