Identification of DNA Repair Genes Involved in Cancer/Aging/Skeletal Abnormalities

~Expected to be used in development of personalized medicine for leukemia or stomach cancer using anti-cancer agents, or novel anti-cancer agents~

 

The research team of Associate Professor Tomoo Ogi of Nagasaki University’s Atomic Bomb Disease Institute and Kazuya Kashiyama of the Graduate School of Biomedical Sciences has discovered that the cause of new diseases associated with three genetic disorders ? Cockayne syndrome characterized by systemic abnormal development with skeletal dysplasia and premature aging, xeroderma pigmentosum which leads to sun sensitivity and skin cancer, and Fanconi's anemia which leads to leukemia and bone marrow function decline ? are due to genetic abnormality of a multifunction DNA repair factor called ERCC1-XPF endonuclease complex (an enzyme that cleaves damage) which acts to remove damage in DNA caused by aldehydes, which are a product of alcohol metabolism, or various anti-cancer agents.

This ERCC1-XPF complex is an essential factor in the repair of interstrand cross-link damage (in which two DNA strands are joined) that occurs in DNA due to administration of anti-cancer agents, and individual differences in this factor are believed to contribute to individual differences in the therapeutic effects and side effects of anti-cancer drugs, or to malignant transformation of cancer due to drug resistance. Because cells from the patients who were subjects showed strong sensitivity to the anti-cancer agent Mitomycin C due to abnormality in the cleaving function of the ERCC1-XPF complex, by carefully analyzing the mechanism by which this complex repairs interstrand cross-link damage, we can expect progress in applied research on the mechanism of the appearance of drug-resistant cancers, the development of new anti-cancer agents, and drug screening to alleviate side effects.

The results of this study will be reported in the American Journal of Human Genetics (May 2013).

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