|
Program Co-Leaders |
|
This program is a joint endeavor involving 35-40 investigators from UCSF and Lawrence Berkeley National Laboratory. It brings together the LBNL emphasis on radiation research and basic understanding of DNA repair mechanisms through applications of advanced technology with basic-science and clinical emphases among UCSF participants.
Available specialized resources include:
- SIBYLS synchrotron beamline at the LBNL Advanced Light Source (ALS), which includes switchable end-stations allowing either protein crystallography optimized for large complexes or Small-Angle X-Ray Scattering for molecular envelope characterization in solution;
- ALS X-ray beamline for irradiation of defined segments of cell culture models;
- expertise in protein expression, purification, and protein-protein interaction studies;
- advanced microscopy techniques and analysis;
- specialized human and murine cell culture models and transgenic mouse models
DNA damage resulting from environmental sources is a ubiquitous threat to genomic integrity. Sources include ultraviolet light (UV), ionizing radiation (IR), and a variety of chemicals, as well as endogenous sources generated by the cellular metabolism. There is considerable overlap between IR-induced damage and endogenously produced lesions, in that both are predominantly the result of oxidation from attack by reactive oxygen species. The resulting DNA lesions include a large variety of altered bases as well as single-strand and double-strand breaks.
The deleterious effects of these lesions are countered by a broad array of crucial DNA-repair mechanisms that detect and remove the damage. Equally important is the coordination of repair processes with defense mechanisms that arrest the cell cycle in response to DNA damage. When DNA repair fails, persisting DNA lesions can result in permanent genetic changes, many of which can be important causative events in carcinogenesis. This relationship is reflected by the extremely high cancer predisposition of individuals with hereditary defects in DNA-repair processes.
The Program integrates multidisciplinary approaches including molecular, biochemical, genetic, cell biological, and structural studies to achieve mechanistic understanding of the molecular machines that maintain genomic integrity. A related focus is the coordination of DNA-repair processes with other cellular events, including transcription, replication, telomere maintenance, DNA-damage signaling, cell cycle control, and apoptosis.
Program research on the biological effects of IR emphasizes interactions of radiation with DNA and chromatin, genetic regulation of radiosensitivity, alterations in gene and protein expression, apoptotic regulation, mechanisms of mutagenesis, induced genomic instability, the adaptive response and bystander effects, cataractogenesis, and CNS effects. Particular interests include elucidating the molecular mechanisms underlying biological responses to low IR doses. Mechanistic research on DNA-repair processes elucidates the molecular mechanisms of base excision repair, nucleotide excision repair, transcription-coupled repair, and double-strand break repair; dissects mechanisms for homologous recombination; characterizes the effect of chromatin modifications on radiosensitivity; and investigates the effect of nuclear scaffold proteins on transcriptional regulation.
The effect of post-translational modifications on protein partnerships, subcellular localization, and regulation of DNA-repair processes is another major focus. In addition, interdisciplinary approaches are employed to investigate the structural cell biology of the five major DNA-repair pathways with the goal of providing molecular descriptions of the dynamic structures of protein machines and complexes acting in damage signaling, damage detection, and repair, together with a hierarchical map of the protein interactions and protein modifications that assemble these machines.
The overall goal is to provide structural and functional insights into cancer etiology, developmental and immunological defects, and premature aging associated with defects in DNA repair and with cellular and tissue responses to radiation damage. Ultimately, investigators hope to translate this knowledge into an informed basis for new cancer diagnostic and therapeutic strategies, including identification of promising molecular targets for cancer drug discovery.
> Read more about the affiliation relationship between the UCSF Helen Diller Family Comprehensive Cancer Center and Lawrence Berkeley National Laboratory.
