The broad objective of this project is to understand both the biochemical mechanism and biological function of DNA helicases. One of the helicases that is a focus of this proposal is distinctive in that it recognizes a specific single-stranded DN sequence while translocating and, in response to that interaction, alters its biochemical behavior in unprecedented ways. The other helicases comprise a broad family of related orthologs and paralogs, the RecQ-family. The RecQ helicases interact specifically with numerous accessory proteins that take advantage of their unique unwinding capacities and that also alter their DNA unwinding capabilities. Finally, a third group of helicases constitutes a heterogeneous collection of helicases that share the common capacity to remodel protein-ssDNA complexes. Understanding the mechanism and function of such motor proteins are goals of this research proposal. In the past decade, it has become possible to reliably examine helicases and DNA motor proteins at the single-molecule level. This capability has transformed mechanistic analysis of this important family of proteins. Single-molecules of these helicases will be imaged to literally visualize the manner by which they bind and release their partner proteins in order to better understand their functions in important biological regulatory processes. We will use both single-molecule and ensemble methods to understand both mechanism and function.
The broad objective of this proposal is to understand both the biochemical mechanism and biological function of DNA helicases. These proteins are involved in various aspects of DNA repair and chromosome maintenance. A major consequence of unrepaired DNA damage is genomic rearrangement that enables tumorigenesis. These proteins are responsible for preserving genetic integrity in all organisms and, when defective in humans, they are responsible for a variety of diseases. Mutations in genes that encode helicases are associated with human pathologies, such as breast cancer and Fanconi's anemia (FANCJ/FANCM); xeroderma pigmentosum (ERCC2 and ERCC3); Cockayne's (ERCC6); Bloom's (BLM); Werner's (WRN); and Rothmund-Thomson (RECQ4) syndromes, revealing connections to disease processes as diverse as cancer, anemia, and premature aging. Consequently, a molecular understanding of these proteins and their analogs is important to human health.
Showing the most recent 10 out of 65 publications
