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DNA Damage and Cellular Stress Responses

Senescence-Dependent MutS Dysfunction Attenuates Mismatch Repair

¹ DNA Repair Research Center and Departments of ² Anatomy, ³ Surgery, ⁴ Physiology, and ⁵ Pharmacology, School of Medicine, Chosun University, Gwangju, Korea; ⁶ Department of Biochemistry, School of Medicine, Yanbian University, Yanji, Jilin, China; ⁷ Department of Biochemistry, College of Medicine Cheju National University, Jeju, Jeju-do, Korea; and ⁸ Department of Anatomy, College of Medicine, Seonam University, Namwon, Korea

Requests for reprints: Ho Jin You, Korean DNA Repair Research Center and Department of Pharmacology, Chosun University School of Medicine, Bio Engineering BD, 2F 375 Seosuk-Dong, Gwangju 501-759, Republic of Korea (South Korea). Phone: 82-62-230-6337; Fax: 82-62-230-6586. E-mail: hjyou{at}chosun.ac.kr

DNA damage and mutations in the genome increase with age. To determine the potential mechanisms of senescence-dependent increases in genomic instability, we analyzed DNA mismatch repair (MMR) efficiency in young and senescent human colonic fibroblast and human embryonic lung fibroblast. It was found that MMR activity is significantly reduced in senescent cells. Western blot and immunohistochemistry analysis revealed that hMSH2 and MSH6 protein (MutS complex), which is a known key component in the MMR pathway, is markedly down-regulated in senescent cells. Moreover, the addition of purified MutS to extracts from senescent cells led to the restoration of MMR activity. Semiquantitative reverse transcription-PCR analysis exhibited that MSH2 mRNA level is reduced in senescent cells. In addition, a decrease in E2F transcriptional activity in senescent cells was found to be crucial for MSH2 suppression. E2F1 small interfering RNA expression reduced hMSH2 expression and MMR activity in young human primary fibroblast cells. Importantly, expression of E2F1 in quiescent cells restored the MSH2 expression as well as MMR activity, whereas E2F1-infected senescent cells exhibited no restoration of MSH2 expression and MMR activity. These results indicate that the suppression of E2F1 transcriptional activity in senescent cells lead to stable repression of MSH2, followed by a induction of MutS dysfunction, which results in a reduced cellular MMR capacity in senescent cells. (Mol Cancer Res 2008;6(6):978–89)