Jayakrishnan Nandakumar
University of Michigan, MI·Biochemistry
Every chromosome in a human or animal cell is a linear piece of DNA, and linear DNA has ends. Those ends create two problems: the cell's DNA repair machinery can mistake a natural end for a broken chromosome and glue chromosomes together, and the ends get a little shorter every time a cell copies its DNA.
- Fields
Biochemistry
Genetics
Biophysics
- Topics
telomeres
shelterin
telomerase
- Grants
- 3 known grants, through Jul 2028
What they work on
- Reconstitute the shelterin proteins of the worm C. elegans outside the cell and determine their structures, to learn how its simpler version of this chromosome-end-protecting complex binds telomeric DNA.
- Test whether the worm counterparts of POT1, a protein that coats single-stranded telomere DNA and guards the double- to single-strand junction, coordinate multiple DNA-binding activities, and whether those activities matter in living worms.
- Determine how TPP1, the shelterin protein that recruits the telomere-extending enzyme telomerase, switches from end-protection mode to end-replication mode during DNA copying, using biochemistry, crystallography and cell biology.
- Dissect how the meiosis-specific TERB1-TERB2-MAJIN complex tethers telomeres to the nuclear envelope while protecting paired chromosomes from unwanted telomeric recombination, and discover new factors involved.
- Determine the structural basis, dynamics and meiosis-specificity of the interaction between KASH5, a nuclear envelope protein, and the motor protein dynein, combining in vitro assays with mouse spermatocytes.
- Map the higher-order assemblies that SUN1-KASH5 forms at the nuclear envelope using single-molecule TIRF microscopy and membrane protein reconstitution, and test how a human KASH5 mutation causes infertility.
More about the research
Special structures called telomeres — DNA plus a set of bound proteins — solve both problems, and a third one too: during the cell divisions that make sperm and eggs, telomeres anchor chromosomes to the edge of the nucleus so matching chromosomes can find each other. Work in this lab asks, at the level of individual protein structures and interactions, how telomeres juggle these jobs, since failures show up in cancer, in inherited diseases of stem cells, and in infertility.
Why it matters
Telomere failure sits behind several human conditions: telomerase is reactivated in most cancers, while too little telomerase activity in stem cells causes telomeropathies, and errors in meiotic chromosome pairing contribute to infertility and miscarriage. By pinning down the molecular switches and interactions that keep chromosome ends protected, replicated and correctly paired, this work could point to drug targets for telomere dysfunction in cancer and inherited disease, and help explain specific infertility-causing mutations for diagnosis.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Dirk Hockemeyer
University of California-Berkeley, CA·Genetics
Use deep scanning mutagenesis of TPP1, a shelterin protein that recruits telomerase, to measure how many variants of uncertain significance from ClinVar change telomere length.
Chenshu Liu
Lehigh University, PA·Genetics
Determine how the force-sensing ion channel Piezo works at the oocyte nuclear envelope to relay a signal that triggers cell death after synapsis fails in the C. elegans germline.
Anne M Villeneuve
Stanford University, CA·Genetics
Uncover the mechanisms that ensure every chromosome pair forms a crossover, an exchange that links matching chromosomes so they separate correctly, in C. elegans meiosis.
The school
University of Michigan: 124 labs on PI Pages, $2.1B a year on research, 963 research doctorates a year.
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