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Chromosome segregation mechanisms and the therapeutic response to anti-mitotic drugs

Cancer cells very frequently exhibit instability of chromosome number, but the molecular origins of aneuploidy, and its significance in cancer pathogenesis and therapy are not clearly understood. We study the fundamental mechanisms that govern chromosome segregation to elucidate how they may be perturbed by genetic alterations that occur during early steps in carcinogenesis, to study how these perturbations affect the response of cancer cells to anti-mitotic agents like taxanes used widely in cancer therapy, and to develop new approaches to improve therapeutic responsiveness in the clinic.

Analyses of mitotic progression and the completion of cell division using RNAi screening, biochemistry and imaging. 

Selected Publications:

Oncogenic KRAS triggers MAPK-dependent errors in mitosis and MYC-dependent sensitivity to anti-mitotic agents. Perera D, Venkitaraman AR. Sci Rep. 2016 Jul 14;6:29741. doi: 10.1038/srep29741.

Diversity-oriented synthesis as a tool for identifying new modulators of mitosis.Ibbeson B.M., Laraia L., Alza E, O' Connor C.J., Tan Y., Davies H.M., McKenzie G., Venkitaraman A.R.*, Spring D.* Nature Commun. (2014) 5:3155

Continuous polo-like kinase 1 activity regulates diffusion to maintain centrosome self-organization during mitosis. Mahen R, Jeyasekharan AD, Barry NP, Venkitaraman AR.Proc Natl Acad Sci USA. 2011 May 31;108(22):9310-5. 

A mitotic function for the high-mobility group protein HMG20b regulated by its interaction with the BRC repeats of the BRCA2 tumor suppressor. Lee M, Daniels MJ, Garnett MJ, Venkitaraman AR. Oncogene. 2011 Mar 14. [Epub ahead of print]

A vertebrate N-end rule degron reveals that Orc6 is required in mitosis for daughter cell abscission. Bernal JA, Venkitaraman AR. J Cell Biol. 2011 Mar 21;192(6):969-78.

UBE2S elongates ubiquitin chains on APC/C substrates to promote mitotic exit.Garnett MJ, Mansfeld J, Godwin C, Matsusaka T, Wu J, Russell P, Pines J, Venkitaraman AR. Nat Cell Biol. 2009 Nov;11(11):1363-9.

The conserved N-terminal region of the mitotic checkpoint protein BUBR1: a putative TPR motif of high surface activity. Bolanos-Garcia VM, Beaufils S, Renault A, Grossmann JG, Brewerton S, Lee M, Venkitaraman A, Blundell TL. Biophys J. 2005 Oct;89(4):2640-9.

Abnormal cytokinesis in cells deficient in the breast cancer susceptibility protein BRCA2. Daniels MJ, Wang Y, Lee M, Venkitaraman AR. Science. 2004 Oct 29;306(5697):876-9.

PML bodies control the nuclear dynamics and function of the CHFR mitotic checkpoint protein. Daniels MJ, Marson A, Venkitaraman AR. Nat Struct Mol Biol. 2004 Nov;11(11):1114-21.

AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol. Anand S, Penrhyn-Lowe S, Venkitaraman AR. Cancer Cell. 2003 Jan;3(1):51-62.

Mitotic checkpoint inactivation fosters transformation in cells lacking the breast cancer susceptibility gene, Brca2. Lee H, Trainer AH, Friedman LS, Thistlethwaite FC, Evans MJ, Ponder BA, Venkitaraman AR. Mol Cell. 1999 Jul;4(1):1-10.