Arshad Desai

Research

We are focused on understanding the pathways and molecular mechanisms that ensure accurate genome inheritance during cell division. Errors in genome inheritance are the cause of birth defects and are implicated in both cancer initiation and progression. In addition, the machinery involved in genome inheritance is a prominent target in cancer chemotherapy. Our interest in cell division stems from a long-standing fascination with the microtubule cytoskeleton, comprised of highly dynamic protein polymers that employ energy from assembly-coupled nucleotide hydrolysis to perform useful work in the cell. This interest led us to focus on the kinetochore, the macromolecular machine assembled on the centromere regions of chromosomes during cell division in order to harness the intrinsic dynamics of microtubule polymers for chromosome segregation.

To study the pathways and mechanisms operating during chromosome segregation, we have developed the early C. elegans embryo as a powerful model for discovery and characterization of the underlying molecular machinery. Our early efforts led to the definition of the core microtubule binding protein network at the kinetochore and the identification of a conserved protein family involved in epigenetic propagation of centromeric chromatin. In more recent work, we have elucidated multiple mechanisms acting in concert with the core microtubule-binding machinery to ensure accurate chromosome segregation and have begun to untangle the complex coupling between mechanical and signaling events at the kinetochore that is critical for accurate segregation.

In addition to our focus on the dynamic kinetochore-microtubule interface and the regulatory mechanisms operating to ensure its correct formation, we are also pursuing projects on the epigenetic basis of centromere identity, and on the checkpoint pathways coordinating chromosome segregation with cell cycle progression. Our findings are relevant to the genesis of cancer genome instability and are leading us to collaboratively explore new mechanism-targeted approaches focused on cell division for cancer therapy. Our use of C. elegans is also leading us to discover new conserved cell division-independent functions for ancient chromosome segregation machinery, e.g. in neurodevelopment.

Select Publications

  • Lara-Gonzalez P, Moyle M, Budrewicz J, Mendoza J, Oegema K, Desai, A. The G2-to-M transition is ensured by a dual mechanism that protects cyclin B from degradation by Cdc20-activated APC/C. Developmental Cell (in press)
  • Cheerambathur DK*, Prevo B*, Chow TL, Hattersley N, Wang S, Zhao Z, Kim T, Gerson-Gurwitz A, Oegema K, Green R, Desai A. 2019. The kinetochore-microtubule coupling machinery is repurposed to direct sensory nervous system morphogenesis. Developmental Cell 48(6):864-872.e7. doi: 10.1016/j.devcel.2019.02.002
  • Kim T*, Lara-Gonzalez P*, Prevo B, Meitinger F, Cheerambathur D, Oegema K, Desai A. Kinetochores accelerate or delay APC/C activation by directing Cdc20 to opposing fates. Genes & Development 2017 31(11):1089-1094.
  • Santaguida S, Richardson A, Iyer DR, M'Saad O, Zasadil L, Knouse KA, Wong Y, Rhind N, Desai A, Amon A. Chromosome mis-segregation generates cell cycle-arrested cells with complex karyotypes that are eliminated by the immune system. 2017. Developmental Cell 41(6):638-651.
  • Cheerambathur DK, Prevo B, Oegema K, Desai A. Dephosphorylation of the Ndc80 tail stabilizes kinetochore-microtubule attachments via the Ska complex. Developmental Cell 2017 41(4):424-437. (#corresponding authors)
  • Hattersley N, Cheerambathur D, Moyle M, Stefanutti M, Richardson A, Lee KY, Dumont J, Oegema K, Desai A. 2016. A nucleoporin docks protein phosphatase 1 to direct meiotic chromosome segregation and nuclear assembly. Developmental Cell 38(5):463-77.
  • Gerson-Gurwitz A, Wang S, Sathe S, Green R, Yeo GW, Oegema K, Desai A. 2016. A small RNA-catalytic Argonaute pathway tunes germline transcript levels to ensure embryonic divisions. Cell 165(2):396-409.
  • Folco HD, Campbell CS, May K, Espinoza C, Oegema K, Ren B, Hardwick K, Grewal S, Desai A. 2015. The N-terminal tail of CENP-A confers epigenetic stability to centromeres via the CENP-T branch of the CCAN in fission yeast. Current Biology 25(3):348-56.
  • Cheerambathur D, Gassmann R, Cook B, Oegema K, Desai A. 2013. Crosstalk between microtubule attachment complexes ensures accurate chromosome segregation. Science 342(6163):1239-1242.
  • Campbell C, Desai A. 2013. Tension sensing by Aurora B kinase is independent of survivin-based centromere localization. Nature 497(7447):118-21.
  • Gassmann R*, Rechtsteiner A*, Yuen K*, Egelhofer T, Muroyama A, Barron F, Maddox P, Monen J, Ercan S, Oegema K, Lieb J, Strome S, Desai A. 2012. An inverse relationship to germline transcription defines centromeric chromatin in C. elegans. Nature 484(7395):534-7.
  • Maddox P, Hyndman F, Monen J, Oegema K, Desai A. 2007. Functional genomics identifies a conserved Myb domain-containing protein family required for assembly of CENP-A chromatin. Journal of Cell Biology 176:757-63.
  • Cheeseman I, Chappie J, Wilson-Kubalek E, Desai A. 2006. The conserved KMN network constitutes the core microtubule-binding site of the kinetochore. Cell 127:983-97.
  • Desai A, Rybina S, Müller-Reichert T, Shevchenko A, Shevchenko A, Hyman A, Oegema K. 2003. KNL-1 directs assembly of the microtubule-binding interface of the kinetochore in C. elegans. Genes & Development 17:2421-35.

Biography

Arshad Desai received his Ph.D. in cell biology from the University of California, San Francisco and conducted postdoctoral work at the European Molecular Biology Laboratory in Heidelberg and the Max Planck Institute for Cell Biology & Genetics in Dresden. He joined the UC San Diego faculty in late 2002 and has been the recipient of a Damon Runyon Scholar Award, the American Society for Cell Biology Early Career Award, and a Keith Porter Fellowship. He is a Senior Editor of the Journal of Cell Biology, has chaired review panels for the National Institutes of Health and the European Research Council, and is a lifetime fellow of the American Society for Cell Biology.