한빛사 논문
Seon Hee Kim1,2,†, Geun Hoe Kim1,2,†, Michael G. Kemp3,4,* and Jun-Hyuk Choi1,2,*
1Biometrology Group, Division of Chemical and Biological Metrology, Korea Research Institute of Standards and Science, Daejeon 305-340, Republic of Korea, 2Department of Bio-Analytical Science, University of Science & Technology, Daejeon 305-340, Republic of Korea, 3Department of Pharmacology and Toxicology, Wright State University Boonshoft School of Medicine, Dayton, OH 45435, USA and 4Dayton Veterans Administration Medical Center, Dayton, OH 45428, USA
*To whom correspondence should be addressed.
†The authors wish it to be known that, in their opinion, the first two authors should be regarded as Joint First Authors.
Abstract
The nucleotide excision repair (NER) machinery removes UV photoproducts from DNA in the form of small, excised damage-containing DNA oligonucleotides (sedDNAs) ∼30 nt in length. How cells process and degrade these byproducts of DNA repair is not known. Using a small scale RNA interference screen in UV-irradiated human cells, we identified TREX1 as a major regulator of sedDNA abundance. Knockdown of TREX1 increased the level of sedDNAs containing the two major UV photoproducts and their association with the NER proteins TFIIH and RPA. Overexpression of wild-type but not nuclease-inactive TREX1 significantly diminished sedDNA levels, and studies with purified recombinant TREX1 showed that the enzyme efficiently degrades DNA located 3′ of the UV photoproduct in the sedDNA. Knockdown or overexpression of TREX1 did not impact the overall rate of UV photoproduct removal from genomic DNA or cell survival, which indicates that TREX1 function in sedDNA degradation does not impact NER efficiency. Taken together, these results indicate a previously unknown role for TREX1 in promoting the degradation of the sedDNA products of the repair reaction. Because TREX1 mutations and inefficient DNA degradation impact inflammatory and immune signaling pathways, the regulation of sedDNA degradation by TREX1 may contribute to photosensitive skin disorders.
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