University of Michigan Chemical Biology Doctoral Program
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.
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.
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.
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.