Role of high mobility group (HMG) chromatin proteins in DNA repair.

While the structure and composition of chromatin not only influences the type and extent of DNA damage incurred by eukaryotic cells, it also poses a major obstacle to the efficient repair of genomic lesions. Understanding how DNA repair processes occur in the context of nuclear chromatin is a current experimental challenge, especially in mammalian cells where the powerful tools of genetic analysis that have been so successful in elucidating repair mechanisms in yeast have seen only limited application. Even so, work over the last decade with both yeast and mammalian cells has provided a rather detailed description of how nucleosomes, the basic subunit of chromatin, influence both DNA damage and repair in all eukaryotic cells. The picture that has emerged is, nonetheless, incomplete since mammalian chromatin is far more complex than simply consisting of vast arrays of histone-containing nucleosome core particles. Members of the "High Mobility Group" (HMG) of non-histone proteins are essential, and highly dynamic, constituents of mammalian chromosomes that participate in all aspects of chromatin structure and function, including DNA repair processes. Yet comparatively little is known about how HMG proteins participate in the molecular events of DNA repair in vivo. What information is available, however, indicates that all three major families of mammalian HMG proteins (i.e., HMGA, HMGB and HMGN) participate in various DNA repair processes, albeit in different ways. For example, HMGN proteins have been shown to stimulate nucleotide excision repair (NER) of ultraviolet light (UV)-induced cyclobutane pyrimidine dimer (CPD) lesions of DNA in vivo. In contrast, HMGA proteins have been demonstrated to preferentially bind to, and inhibit NER of, UV-induced CPDs in stretches of AT-rich DNA both in vitro and in vivo. HMGB proteins, on the other hand, have been shown to both selectively bind to, and inhibit NER of, cisplatin-induced DNA intrastrand cross-links and to bind to misincorporated nucleoside analogs and, depending on the biological circumstances, either promote lesion repair or induce cellular apoptosis. Importantly, from a medical perspective, the ability of the HMGA and HMGB proteins to inhibit DNA repair in vivo suggests that they may be intimately involved with the accumulation of genetic mutations and chromosome instabilities frequently observed in cancers. Not surprisingly, therefore, the HMG proteins are being actively investigated as potential new therapeutic drug targets for the treatment of cancers and other diseases.