Embryonic stem cells lacking the epigenetic regulator Cfp1 are hypersensitive to DNA-damaging agents and exhibit decreased Ape1/Ref-1 protein expression and endonuclease activity |
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| Authors: | Courtney M. Tate Melissa L. Fishel Julianne L. Holleran Merrill J. Egorin David G. Skalnik |
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| Affiliation: | 1. College of Pharmacy, Ajou University, 206, Worldcup-ro, Yeongtong-gu, Suwon 443-749, Republic of Korea;2. Research Institute of Pharmaceutical Sciences and Technology, Ajou University, 206, Worldcup-ro, Yeongtong-gu, Suwon 443-749, Republic of Korea;3. Department of Pharmacology, Yonsei University, College of Medicine, 50, Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea;1. University of South Carolina School of Medicine, Department of Pathology, Microbiology, and Immunology, Columbia, SC 29209, USA;2. Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA;1. Department of Cardiovascular Disease, Affiliated Hospital, Luzhou Medical College, Luzhou, China;2. Department of Vascular Surgery, Affiliated Hospital, Luzhou Medical College, Luzhou, China;3. Department of Urology, Affiliated Hospital, Luzhou Medical College, Luzhou, China;4. Department of Endocrinology, Affiliated Hospital, Luzhou Medical College, Luzhou, China;1. Gannan Medical University, Ganzhou, Jiangxi, China;2. College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, China;3. Jiangxi Provincial People''s Hospital, Nanchang, Jiangxi, China;4. Flaum Eye Institute and Department of Ophthalmology, University of Rochester, Rochester, NY, USA;1. Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA;2. Division of Pharmacology, The Ohio State University, Columbus, OH 43210, USA |
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| Abstract: | Modulation of chromatin structure plays an important role in the recruitment and function of DNA repair proteins. CXXC finger protein 1 (Cfp1), encoded by the CXXC1 gene, is essential for mammalian development and is an important regulator of chromatin structure. Murine embryonic stem (ES) cells lacking Cfp1 (CXXC1?/?) are viable but demonstrate a dramatic decrease in cytosine methylation, altered histone methylation, and an inability to differentiate. We find that ES cells lacking Cfp1 are hypersensitive to a variety of DNA-damaging agents. In addition, CXXC1?/? ES cells accumulate more DNA damage and exhibit decreased protein expression and endonuclease activity of AP endonuclease (Ape1/Ref-1), an enzyme involved in DNA base excision repair. Expression in CXXC1?/? ES cells of either the amino half of Cfp1 (amino acids 1–367) or the carboxyl half of Cfp1 (amino acids 361–656) restores normal Ape1/Ref-1 protein expression and rescues the hypersensitivity to DNA-damaging agents, demonstrating that Cfp1 contains redundant functional domains. Furthermore, retention of either the DNA-binding activity of Cfp1 or interaction with the Setd1A and Setd1B histone H3-Lys4 methyltransferase complexes is required to restore normal sensitivity of CXXC1?/? ES cells to DNA-damaging agents. These results implicate Cfp1 as a regulator of DNA repair processes. |
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