Abstract B53: Chromatin remodeling as a new target for cancer chemoprevention

Abstract

Abstract Chromatin remodeling complexes use the energy of ATM hydrolysis to dynamically regulate the structure of chromatin. Growing evidence indicates that these complexes have a widespread role in tumor suppression. However, the mechanisms by which aberrations in these complexes drive tumorigenesis remain largely unknown. In addition to their well-established role in gene transcriptional control, our recent studies provide a novel linkage between chromatin remodeling and homologous recombination (HR)-mediated DNA repair in the maintenance of genomic stability. Our results showed that an evolutionarily conserved chromatin remodeling complex SWI/SNF is targeted to DNA damage lesions via an interaction with BRIT1, an early DNA damage responsive protein. Chromatin remodeling activity is required for relaxing highly condensed chromatin and facilitating the loading of HR repair proteins to conduct efficient HR repair. Furthermore, our unpublished data identified that another remodeling complex CHD4 functions as an upstream regulator of HR repair by recruiting BRIT1 and BRCA1 to DNA lesions. As a functional consequence of impaired HR repair, our data indicated that cells with depletions of chromatin remodeling complexes SWI/SNF and CHD4 show hypersensitivity to a new class of drugs poly ADP ribose polymerase (PARP) inhibitors via a synthetic lethal interaction. In conclusion, our studies reveal the interplay between epigenetic regulation and genome maintenance. Chromatin remodeling affects HR repair process, which may lead to the changes in the DNA coding sequencing that are inheritable through cell division. Moreover, Deficient HR repair has been well known to predispose to cancer development, which is highlighted by mutations of HR repair genes BRCA1/BRCA2 in breast and ovarian cancers. Our findings may have important clinical implications in cancer prevention. Chromatin remodeling complexes, such as SWI/SNF and CHD4 might be used as epigenetic markers for prognosis, and prediction in early stage of tumorigenesis, and also for targeted preventive intervention by using PARP inhibitors. Citation Information: Cancer Prev Res 2011;4(10 Suppl):B53.