When you are trying to make drugs that treat cancer, it is helpful to know the structures that would make good targets. The Nandakumar Lab has now published in Proceedings of National Academy of Sciences (PNAS) a structural model of a prime cancer target—the interface of the enzyme telomerase and a protein at the end of chromosomes, TTP1.
Telomeres protect the ends of chromosomes and keep them from fusing improperly with other chromosomes. In normal cell division to regenerate tissue and counteract aging, the enzyme telomerase catalyzes DNA synthesis at the telomere to prevent shortening and loss of critical information.
Cancer cells are also actively dividing and making telomerase though most body cells do not make telomerase. “It is a unifying feature of most cancers, but is absent in normal non-dividing cells of our body,” explains JK Nandakumar, associate professor of molecular, cellular, and developmental biology. “Therefore, telomerase is a prime target for anti-cancer drug discovery, but there is no high resolution structure of human telomerase to guide such efforts.”
The protein TPP1 recruits telomerase to telomeres. “We previously mapped the regions of TPP1 that bind telomerase. Now, we have identified telomerase regions that bind TPP1.”
“Our studies provide a functionally validated structural model for the telomerase-TPP1 interface, setting the stage for its high-resolution structure and its targeting for anti-cancer purposes.”
The lab takes a multi-pronged approach integrating structural, biochemical and cytological techniques that each feed into one another to develop their molecular model of how telomeres and telomerase perform their critical functions. For this study they used a combination of protein-protein hybrids, protein fusions, and domain deletions, and a mutagenesis screen.
TPP1 Takes Various Forms
Earlier this year the Nandakumar Lab published an article in Cell Reports that showed that TPP1 comes diffrent forms in different tissues. “We discovered that TPP1 can exist in two protein forms: TPP1-long (TPP1-L) and TPP1-short (TPP1-S).”
Somatic cells including somatic stem cells contain almost exclusively TPP1-S, which allows telomerase in somatic stem cells to sustain cell division and regenerate tissues to counter aging.
The small number of mature germ cells that reside in the male testes and give rise to sperm contain mostly TPP1-L, which inhibits unnecessary telomere elongation by telomerase in mature germ cells.
“Our study shows how opposing functions --telomerase stimulation vs. inhibition-- can be exhibited by the same gene for specific outcomes in different tissues,” Nandakumar continues. “It also shows how the number of genes annotated in the human genome greatly underestimates the full repertoire of possible functions.”
The project also demonstrates why Nandakumar says the University of Michigan “provides the perfect environment for collaborations.” The Nandakumar Lab in MCDB partnered with Assistant Professor Sue Hammoud’s lab in Human Genetics for this study.
”We are two junior labs in different schools that have never interacted before this project. However the intersection of telomere biology--our expertise-- and germ cell biology --Hammoud's expertise-- brought us together and resulted in a successful collaboration.”
Students from both labs are authors on this paper.
PNAS: Combining conservation and species-specific differences to determine how human telomerase binds telomeres.
Tesmer VM, Smith EM, Danciu O, Padmanaban S, Nandakumar J.
Proc Natl Acad Sci U S A. 2019 Dec 10. pii: 201911912. doi: 10.1073/pnas.1911912116. [Epub ahead of print]
Cell Reports: Two separation-of-function isoforms of human TPP1 dictate telomerase regulation in somatic and germ cells Sherilyn Grill, Kamlesh Bisht, Valerie M. Tesmer, Adrienne Niederriter Shami, Saher S. Hammoud, Jayakrishnan Nandakumar Cell Reports, Vol. 27, Issue 12, p3511–3521.e7 Published in issue: June 18, 2019