725 N. Wolfe Street
Baltimore, MD 21205
Molecular mechanisms underlying accurate chromosome segregation and centrosome duplication
Cell division is a fundamental process forming the basis for life itself. Each time a cell divides, it makes a complete copy of its entire genome and segregates this genome such that both daughter cells receive all the genetic information required for further growth and development. Errors in the distribution of chromosomes during mitosis lead to the production of cells with an abnormal chromosome content, which in early development lead to lethal growth defects and may later contribute to the development of cancer.
The Holland lab is investigating in the molecular mechanisms that control accurate chromosome distribution and the role that mitotic errors play in human health and disease. Our work utilizes a combination of chemical biology, biochemistry, cell biology and genetically engineered mice to study pathways involved in mitosis and their effect on cell and organism physiology. A major focus of the group is to develop cell and animal-based models to study the role of cell division defects in genome instability and tumorigenesis.
Lambrus, B.G., Daggubati, V., Uetake, Y., Scott, P.M., Clutario, K.M., Sluder, G., Holland, A.J. (2016) A USP28-53BP1-p53-p21 signaling axis arrests growth following centrosome loss or prolonged mitosis. Journal of Cell Biology 214:143-153. [ link ] [ pdf ]
Lambrus BG, Uetake Y, Clutario KM, Daggubati V, Snyder M, Sluder G, Holland AJ. (2015) p53 protects against genome instability following centriole duplication failure. Journal of Cell Biology 210(1), 63-77. [ pdf ]
Moyer TC, Clutario KM, Lambrus BG, Daggubati V, Holland AJ. (2015) STIL binding to Plk4 activates kinase activity to promote centriole duplication. Journal of Cell Biology. 209(6), 863-78. [ pdf ]
Holland AJ, Fachinetti D, Zhu Q, Bauer M, Verma IM, Nigg EA, Cleveland DW. (2012) The autoregulated instability of Polo-like kinase 4 limits centrosome duplication to once per cell cycle. Genes and Development 26, 2684-2689. [ link ]
Holland AJ*, Fachinetti D*, Cleveland DW. (2012) An inducible system for the rapid and complete destruction of proteins in mammalian cells. Proceedings of the National Academy of Sciences USA 109, E3350-E3357. [ link ]
Holland AJ, Cleveland DW. (2012) Chromoanagenesis and cancer: mechanisms and consequences of localized, complex chromosomal rearrangements. Nature Medicine 18, 1630-1638. [ link ]
Holland AJ, Cleveland DW. (2012) Losing balance: the origin and impact of aneuploidy in cancer. EMBO Reports 13, 501-514. [ link ]
Kim Y*, Holland AJ*, Lan W, Cleveland DW. (2010). Aurora kinases and protein phosphatase 1 mediate chromosome congression through regulation of CENP-E. Cell. 142, 444-455. [ link ]
Holland AJ, Lan W, Niessen S, Hoover H, Cleveland DW. (2010). Polo-like kinase 4 kinase activity limits centrosome overduplication by autoregulating its own stability. Journal of Cell Biology. 188, 191-198. [ link ]