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New Scholar Award in Aging
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Jeff J.
Sekelsky,
Ph. D.
University of North Carolina - Chapel Hill
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Functional Characterization of a Drosophila RecQ Helicase
Genome instability has long been proposed to be a major factor in the aging process. The contribution of genome instability to aging is underscored by the finding that several of the segmental progeroid syndromes, which are characterized by early onset of conditions normally associated with aging, are associated with genome instability. Two such diseases, Werner syndrome and Rothmund-Thomson syndrome, are caused by mutations in genes that encode proteins related to E. coli RecQ. RecQ is a DNA helicase, an enzyme that uses energy from the hydrolysis of nucleotide triphosphates to disrupt the base-pairing between nucleic acid strands to convert double-stranded nucleic acids to single strands. Helicases are essential for virtually all aspects of nucleic acid metabolism - replication, transcription, translation, repair, and recombination.
Studies of RecQ helicases in bacteria and fungi have yielded important insights into the functions of these proteins, though many questions remain. One issue that these studies cannot address, however, is the divergence of these genes into a family in metazoans. In addition to the Werner and Rothmund-Thomson genes mentioned above, three other human RecQ helicase genes have been described. One of these also causes a hereditary disorder (Bloom syndrome) when mutated. Thus, at least three of the five human RecQ helicase genes are associated with diseases. Although these diseases are clinically dissimilar, all three are associated with genome instability and increased risk of cancers. It is unclear what cellular defects underlie the genome instabilities or the clinical manifestations of these diseases.
To help understand cellular and organismal functions of RecQ helicases, we are characterizing a Drosophila melanogaster RecQ helicase using a combination of genetic, cell biological, and biochemical approaches. RecQ5 encodes the Drosophila ortholog of human RECQ5. We have mutated the Drosophila gene and are analyzing the characteristics of the mutants to determine what processes require RecQ5. Drosophila RecQ5 exists in two very different isoforms, produced by alternative splicing. This feature is conserved in the human gene, which indicates that there are probably important functions of the different isoforms. We are investigating the functional significance of the different isoforms. By coupling these genetic studies with biochemical studies of the protein, we hope to gain insight into the functions of RecQ helicases and the consequences of their loss.
Contact
Dr. Sekelsky.
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