Identifying the roles of DNA rewinding enzymes on maintaining genome stability

Dana-Farber Cancer Inst, Boston MA

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Abstract

? DESCRIPTION (provided by applicant): The structure and integrity of our genetic material is of great biological significance. DNA is a dynamic molecule and it is essential to identify and to characterize the enzymes that alter DNA structure. DNA helicases are ATP-driven motor proteins that unwind DNA, and help load single-stranded DNA binding proteins, such as RPA, onto the DNA. In contrast, the human HepA-related protein (HARP) and Annealing Helicase 2, distant members of the SNF2 family of helicase-like proteins, act in an opposite manner to helicases and rewind DNA back into its double-stranded form. The biological importance of HARP has been underscored by the discovery that mutations in the harp gene cause a rare autosomal, recessive, and pleiotropic disorder known as Schimke immuno-osseous dysplasia (SIOD). Both HARP and AH2 interact with proteins involved in DNA replication and repair. Cells lacking HARP and AH2 are more sensitive to DNA damaging agents, suggesting they are required for efficient DNA repair. Our long term objectives are to identify the specific DNA repair pathways that require HARP and AH2, and to determine if they can be manipulated for cancer therapy. The aims of the proposed study are: (1) to investigate the biochemical and cellular functions of HARP and AH2 in their native complexes, (2) to develop new methods and approaches for the study of annealing helicases, and (3) to discover new annealing helicases. This work should provide a strong foundation of knowledge, which we anticipate will lead to future biomedical applications of these new enzymes. Thus, our proposed study is highly significant because it will help elucidate novel mechanisms linking DNA structure with genome stability, DNA repair, and SIOD.