725 N. Wolfe Street
Baltimore MD 21205
Molecular mechanisms underlying accurate chromosome segregation
Since Flemming introduced the term “mitosis” over 100 years ago, a challenge has been to understand how cells divide and faithfully transmit chromosomes at each cell division. 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. My laboratory studies 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.
Centrosome biogenesis and copy number control
Centrosomes are major microtubule organizing centers that play an important role in mitosis where they organize the two poles of the bipolar microtubule spindle apparatus upon which chromosomes are segregated. At the beginning of the cycle, cells contain exactly one centrosome that duplicates once, and only once, before the next cell division, to ensure that cells possess only two centrosomes when they divide. The acquisition of more than two centrosomes leads to errors in spindle assembly that can give rise to aneuploid progeny. Moreover, cancer cells often have extra centrosomes that contribute to the genomic instability characteristic of this disease. Centrosomes and chromosomes are the only two structures in mammalian cells whose copy number is precisely controlled, through a once per cell cycle duplication event and equal segregation into the daughter cells during mitosis. We are interested in dissecting the molecular mechanisms that allow the creation of a single centrosome per cell cycle and determining role that supernumerary centrosomes play in the development of cancer.
Evans LT, Anglen T, Scott P, Lukasik K, Loncarek J, Holland AJ. ANKRD26 recruits PIDD1 to centriolar distal appendages to activate the PIDDosome following centrosome amplification. EMBO J. 2020 Dec 22. doi: 10.15252/embj.2020105106. PMCID: PMC7883295.
Phan T, Maryniak AL, Boatwright CA, Lee J, Atkins A, Tijhuis A, Spierings DCJ, Bazzi H, Foijer F, Jordan PW, Stracker TH, Holland AJ. Centrosome defects cause microcephaly by activating the 53BP1-USP28-TP53 mitotic surveillance pathway. EMBO J. 2020 Jan 4;40(1):e106118. PMCID: PMC7780150.
Yeow ZY*, Lambrus BG*, Marlow R, Zhan KH, Durin M, Evans LT, Scott PM, Phan T, Park E, Ruiz LA, Moralli D, Knight EG, Badder LM, Novo D, Haider S, Green CM, Tutt ANJ, Lord CJ, Chapman JR, Holland AJ. Targeting TRIM37-driven centrosome dysfunction in 17q23-amplified breast cancer. Nature. 2020. Sept;585(7825):447-452. PMCID: PMC7597367. *equal contribution.
Park E, Scott PM, Clutario KM, Anglen T, Cassidy KB, Gerber SA, Holland AJ. WB11 is required for splicing the TUBGCP6 pre-mRNA to promote centriole duplication. J Cell Biol. 2020. Jan 6;219. PMCID: PMC7039186
Mercey O*, Levine MS*, LoMastro G, Rostaing P, Brotslaw E, Gomez V, Kumar A, Spassky N, Mitchell BJ, Meunier A#, Holland AJ. Massive centriole production can occur in the absence of deuterosomes in multiciliated cells. Nat Cell Biol. 2019. Dec; 21(12). PMCID: PMC6913274. *equal contribution.
Moyer TC, Holland AJ. Plk4 Phosphorylates STIL to promote CPAP binding and procentriole formation. eLIFE. 2019. May 22;8. PMCID: PMC6570480
Once and only once: mechanisms of centriole duplication and their deregulation in disease. Nigg, E.A., Holland, A.J. Nature Reviews Molecular Cell Biology 19(5): 297-312. (2018).
Levine, M.S., Bakker, B., Boeckx, B., Moyett, J., Lu, J., Vitre, B., Spierings, D.C., Lansdorp, P.M., Cleveland, D.W., Lambrechts, D., Foijer, F. and Holland, A.J. 2017, Centrosome amplification is sufficient to promote spontaneous tumorigenesis in mammals. Developmental Cell 40(3): 313-22.
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.