In need of repair

As a result of the rapid social and industrial development that occurred in the 20th Century, genomic DNA is now afflicted with increasing amounts of damage caused by various endogenous and environmental agents. DNA lesions can interfere with nucleic acid metabolism (DNA replication, transcription and recombination) as well as with other important cellular functions, such as the cell division cycle. To maintain the integrity of the genome, all organisms contain DNA repair pathways that efficiently remove DNA lesions. In recent years, research on DNA repair has attained widespread recognition and interest appropriate to its fundamental importance in genomic maintenance. DNA repair pathways tend to be specific for a given class of damage. Mismatches or structural abnormalities at replication forks are repaired by the mismatch repair (MMR) pathway; double-stranded breaks are repaired by the recombination process; damaged bases are usually fixed by base excision repair (BER); and bulky or helixdistorting DNA lesions induced by environmental agents – such as the UV component of sunlight – are repaired exclusively by the nucleotide excision repair (NER) pathway. For a variety of reasons, it is essential that researchers fully characterize each of these repair mechanisms. For example, aberrations in DNA repair pathways can result in genetic diseases that are associated with a high susceptibility to cancer. Thus, a detailed understanding of the altered DNA repair pathway should yield insights into these genetic diseases and cancer. Also, a mechanistic blueprint of the various DNA pathways might pave the way for the development of cancer treatments designed to inhibit DNA repair pathways specifically in cancer cells. This Minireview series examines recent progress in functional and structural research on DNA repair pathways. The first review surveys molecular interactions among NER factors. In order to achieve the versatility and specificity required for the recognition and repair of diverse DNA lesions in the context of genomic DNA, NER proteins interact with one another in a dynamic manner via well-defined functional and ⁄or structural domains. Furthermore, this modular nature of NER proteins facilitates crosstalk between NER and other cellular pathways. Also presented in this review are results from recent studies on the structures of and functional interactions among xeroderma pigmentosum proteins and other NER components. The second review in this series describes the functions of MMR proteins. Although these proteins are evolutionally well conserved, they seem to display more diverse biological functions in eukaryotic cells relative to prokaryotes. The authors review structural and functional studies on prokaryotic MMR proteins and describe various newly defined functions associated with eukaryotic MMR proteins, including DNA damage surveillance and diversification of antibodies. The third review is dedicated to the BER system and focuses on the mechanisms by which certain types of DNA damage specify the activation of a specific repair subpathway. The authors also discuss how the shortpatch BER pathway may have difficulty handling certain types of lesions, such as the C1¢-oxidized abasic residue, 2-deoxyribonolactone. Finally, the mechanisms by which long-patch BER mends damaged DNA are described. The fourth and final review discusses a specific example of DNA damage signaling, an intriguing consequence of DNA injury. The ataxia telangiectasia mutated (ATM) protein, which is activated in response to DNA strand breakage, phosphorylates the Nbs1 protein, one of the members of the Mre11–Rad50–Nbs1 (MRN) complex. The authors summarize recent research which reveals that Nbs1 acts both as (a) a downstream target of ATM during the S-phase checkpoint of the cell cycle and (b) an upstream modulator of ATM during the DNA damage response. We expect that this Minireview series will serve to illustrate the significance of recent advances in our understanding of DNA repair mechanisms and help to address many unresolved questions in this burgeoning area of investigation.