Faculty

Jayakrishnan Nandakumar

Assistant Professor of Molecular, Cellular and Developmental Biology

PostDoc, University of Colorado - Boulder
Ph.D., Memorial Sloan-Kettering Cancer Center, Cornell University
M.S., Indian Institute of Science, India
B.S., Calcutta University

Research Focus: Telomerase, Telomeres, Cancer, Aging Biochemistry

Techniques: Biochemistry, Enzymology, Crystallography Cancer Cell Biology

Phone: 734.647.9152
E-mail: jknanda@umich.edu

Telomeres (protein-DNA complex) and telomerase (protein-RNA enzymatic complex) are specialized protein-nucleic acid complexes found at the ends of chromosomes. They play vital roles in ensuring genome stability and stem cell viability, respectively. Additionally, illicit activation of telomerase is a hallmark of a overwhelming majority of cancers, qualifying this enzyme as a prime target for anti-cancer drug development. We use biochemical, cell biological and X-ray crystallographic tools to understand how these complexes are assembled in cells and how they perform their critical biological functions at chromosome ends.

Chromosome end protection

What does one mean by chromosome end protection? Our cells are equipped with a molecular ‘rescue team’ collectively known as the DNA damage response and repair machinery, which heals and seals deleterious double-stranded (ds) breaks to restore genome integrity. Now, if one looks at a natural chromosome end, it looks very much like a double-stranded break. However, if the DNA damage-response machinery gets recruited to natural ends of chromosomes, it would lead to catastrophic inter-chromosomal end-to-end fusions. Hence, the protection of the natural ends of chromosomes from the DNA damage response machinery defines chromosome end protection.
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So, how do we protect chromosomes ends? A six-protein complex known as shelterin that binds specifically to chromosome ends and protects them from end-to-end fusions performs this function in humans and other mammals. Our lab is interested in using a wide array of biochemical, crystallographic, and cell biological tools to determine the mechanisms by which end protection is established.

 

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Chromosome end replication

What is meant by chromosome end replication? After every round of DNA synthesis by DNA polymerases in a given cell cycle, a small fraction of DNA at the extreme end of the chromosome is lost. This is called the end replication problem, which is of great significance because if chromosomes shrink beyond a certain threshold, cells would cease to divide. Although most cells that make up our body are non-dividing and hence do not have to deal with this problem, our stem cells -- which are actively dividing cells responsible for replenishing and repairing tissues – require solution of the end replication problem.

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So, what solves the end replication problem? Telomerase, a specialized RNA-protein (RNP) enzyme, synthesizes DNA repeats (known as telomeric DNA) at chromosome ends to compensate for the DNA lost every cell cycle. Although telomerase plays the ‘good cop’ in facilitating stem cell function, telomerase is illicitly employed by ~90% of cancers for their continued growth and division. Hence, telomerase is considered a major target for anti-cancer drug development. Our lab is interested in using a multi-disciplinary approach combining structural and functional methodologies to answer the several outstanding questions in telomerase biogenesis and action. Macintosh HD:Users:jayakrishnannandakumar:Documents:UMich-startup:webpage:fig-for-face-page:endreplication:Slide1.jpg

 

 

 

 

 

 

 

 

 

 

 

Awards

2012-2016 NIH / NCI K99/R00 Pathway to Independence Award
2009-2012
Helen Hay Whitney Foundation Postdoctoral Fellowship
2006
Lappin Horsfall, Jr. Fellowship Top Graduate Student Prize (Sloan-Kettering Institute)
2005
Julian Rachele Prize top graduate student prize (Weill-Cornell Graduate school)

 

Representative Publications

  1. Kocak, H., Ballew, B. J., Bisht, K., Eggebeen, R., Hicks, B. D., Suman, S., O'Neil, A., Giri, N., Laboratory, N. D. C. G. R., Group, N. D. C. S. W., Maillard, I., Alter, B. P., Keegan, C. E., Nandakumar, J.* and Savage, S. A.*, Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1. Genes Dev 28, 2090-2102, (2014). * Corresponding author

  2. Nandakumar, J. and Cech, T. R., Finding the end: recruitment of telomerase to telomeres. Nat Rev Mol Cell Biol 14, 69-82 (2013)

  3. Nandakumar, J., Bell, C.F., Weidenfeld, I., Zaug, A. J., Leinwand, L.A., and Cech, T. R., The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity. Nature 492, 285-289 (2012).

  4. Nandakumar, J., Podell, E. R., and Cech, T. R., How telomeric protein POT1 avoids RNA to achieve specificity for single-stranded DNA. Proc Natl Acad Sci U S A 107, 651-656 (2010).

  5. Nandakumar, J., Schwer, B., Schaffrath, R., and Shuman, S., RNA repair: an antidote to cytotoxic eukaryal RNA damage. Mol Cell 31, 278-286 (2008).

  6. Nandakumar, J., Nair, P. A., and Shuman, S., Last stop on the road to repair: structure of E. coli DNA ligase bound to nicked DNA-adenylate. Mol Cell 26, 257-271 (2007).

  7. Nandakumar, J., Shuman, S., and Lima, C. D., RNA ligase structures reveal the basis for RNA specificity and conformational changes that drive ligation forward. Cell 127, 71-84 (2006).

  8. Nandakumar, J. and Shuman, S., How an RNA ligase discriminates RNA versus DNA damage. Mol Cell 16, 211-221 (2004).

  9. Mehta, G. and Nandakumar, J., Novel tandem ring-opening/ring-closing metathesis reactions of functionalized cyclohexenoids derived from (-)-alpha-pinene. Tetrahedron Letters 43, 699-702 (2002).

  10. Mehta, G. and Nandakumar, J., Restructuring alpha-pinene: novel entry into diverse polycarbocyclic frameworks. Tetrahedron Letters 42, 7667-7670 (2001).

 

Presentations

  1. New York Structural Biology Group meeting at Cold Spring Harbor Laboratory, NY

  2. Signalling & Cellular Regulation (SCR) group mini-symposium University of Colorado,  Boulder

 

 

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