Senior Scholar Award in Aging
Sherman M. Weissman, M.D.
Yale University School of Medicine

The Molecular/Physiological Basis for Accelerated Aging in the Werner's Syndrome

The Werner syndrome is a human genetic disorder associated with premature onset of symptoms resembling extreme aging. The disease is caused by a mutation in a helicase, but the specific cellular processes that are impaired by the absence of the helicase and the relationship of this impairment to the problems associated with normal aging are unknown. We have been investigating the possibility of a relationship between Werner protein function and telomere maintenance or telomerase functions. One possibility is that Werner protein functions as part of the apparatus that normally replicates telomeric DNA. We have found that Werner protein associates with the 50 kD subunit of human delta DNA polymerase, the polymerase responsible for the bulk of DNA elongation during cellular replication. This association appears to involve the DNA polymerase holoenzyme, and excess Werner protein can segregate delta DNA polymerase in nucleoi. In further studies we have found that transfected telomerase catalytic subunit can be concentrated in the nucleolus in a cell cycle regulated function and that this occurs independently of the presence or absence of the RNA component of the enzyme. We are currently investigating the protein signals responsible for this localization, its relationship to enzyme activation, and any possibility that the localization is modulated by Werner protein.

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