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Research
Normal metabolism leads to the production of reactive oxygen species (ROS). Excessive ROS can attack and damage DNA to directly produce DNA single-strand breaks, one of the most common DNA lesions that occurs within the cell. Because neurons in the central nervous system use a substantial amount of oxygen during normal function, they are especially susceptible to DNA damage caused by the oxidative effects of ROS. Consequently, neurons require efficient DNA-repair mechanisms to deal with these types of lesions. Oxidative stress–induced DNA damage is usually mended via base-excision repair. In the nucleus, a key component of base-excision repair is the Xrcc1 scaffold protein, which binds DNA ligase III (Lig3), and the loss of Xrcc1 leads to a concomitant reduction in Lig3 levels, highlighting the direct relationship between these two proteins.
Although the bulk of cellular DNA is present in the nucleus, the mitochondria also contain an important genome. Mitochondrial DNA (mtDNA) is relatively small and encodes components required for energy production, though full mitochondrial function involves many proteins that are encoded by nuclear DNA. The environment of the mitochondria is highly oxidative; thus, mtDNA is more susceptible to damage than is nuclear DNA. A mitochondrial form of Lig3 also exists, but it functions independently of Xrcc1. Consequently, Lig3 potentially helps repair both nuclear DNA and mtDNA, but the enzyme’s relative contribution to DNA stability in either compartment has been unclear.
Peter J. McKinnon, PhD (Genetics), and colleagues are working to further understand these DNA-repair processes. In a recent article in Nature1, they reported the development of animal models in which DNA-repair factors could be switched off at different times and in different tissues. In this study, the key base-excision repair components, Xrcc1 and Lig3, were separately inactivated throughout the brain. Although biochemical evidence accumulated over many years indicated that the inactivation of Lig3 or Xrcc1 should cause comparable biological defects, the investigators found profound differences in the roles of these two DNA-repair factors.
When Xrcc1 was inactivated in the mouse’s central nervous system, a resulting nuclear DNA–repair deficit was apparent. In contrast, disabling Lig3 did not affect nuclear DNA repair but instead resulted in mtDNA loss, leading to profound mitochondrial dysfunction and incapacitating ataxia. In addition, specific features of Xrcc1-deficient animals, such as the defective generation of certain classes of cerebellar neurons, were absent from Lig3-deficient animals.
Dr. McKinnon’s team concluded that Xrcc1 and Lig3 have distinct biological functions in the mammalian central nervous system: Xrcc1 has an essential role in DNA repair in the nucleus, and Lig3 maintains mtDNA in the mitochondria. This study has refined our understanding of DNA repair and how the cell maintains genome stability in both the nucleus and mitochondria.
Because instability of nuclear DNA or mtDNA can result in diverse human diseases, including cancer, diabetes, and neurodegenerative disorders, understanding the processes that maintain genome stability is of fundamental importance. Moreover, because many anticancer drugs act by damaging DNA, a comprehensive understanding of DNA-repair mechanisms will be important as more effective therapeutic strategies to target cancer are developed.
1Gao Y, Katyal S, Lee Y, Zhao J, Rehg JE, Russell HR, McKinnon PJ. DNA ligase III is critical for mtDNA integrity but not Xrcc1-mediated nuclear DNA repair. Nature Mar 10;471(7337):240-4, 2011. PubMed PMID: 21390131; PubMed Central PMCID: PMC3079429. Abstract | Full Text
Photo: Peter McKinnon, PhD
