유전자 돌연변이를 억제하는 물질을 개발하고자 유전자 돌연변이를 인식하는 센서 물질, 유전자 돌연변이를 억제시키는 유전자 복구 시스템의 조절 물질 흐리고 유전자 복구 단백질에 의한 세포 사멸사 조절 연구를 수행하여 다음과 같은 연구 결과를 얻었음. DNA 손상 및 돌연변이를 인지하는 새로운 유전자 손상 센서에 관여하는 단백질을 규명하고 이 단백질이 유전자 손상 감시시스템에 관여하여 유전자 손상에 대한 보호효과를 수행함을 규명하였음. DNA 수복단백질 활성조절에 관여하는 전사인자 및 세포 내 신호전달 시스템을 규명하였음.
유전자 돌연변이를 억제하는 물질을 개발하고자 유전자 돌연변이를 인식하는 센서 물질, 유전자 돌연변이를 억제시키는 유전자 복구 시스템의 조절 물질 흐리고 유전자 복구 단백질에 의한 세포 사멸사 조절 연구를 수행하여 다음과 같은 연구 결과를 얻었음. DNA 손상 및 돌연변이를 인지하는 새로운 유전자 손상 센서에 관여하는 단백질을 규명하고 이 단백질이 유전자 손상 감시시스템에 관여하여 유전자 손상에 대한 보호효과를 수행함을 규명하였음. DNA 수복단백질 활성조절에 관여하는 전사인자 및 세포 내 신호전달 시스템을 규명하였음. 산화성 세포손상에 의하여 세포 사멸사가 발생할 때 이를 억제하는 유전자 복구단백질의 세포 보호효과를 규명하고 이들에 의한 세포 사멸사 억제 기작을 규명하였음. 산화성 손상에 의한 유전자 돌연변이를 억제하는 세포내 물질인 MT-III의 역할을 규명하였음. 본 연구를 통하여 규명된 연구결과는 유전자 돌연변이 관련 질환 치료 및 예방 약물개발에 기여할 것으로 판단됨.
Abstract▼
Cells must deal with thousands of DNA lesions per day. The majority are mediated by exogenous agents, such as chemicals or ionizing radiation, as well as by endogenous damage, created from the byproducts of metabolism, including reactive species, spontaneous depurination of the DNA strands, and DNA
Cells must deal with thousands of DNA lesions per day. The majority are mediated by exogenous agents, such as chemicals or ionizing radiation, as well as by endogenous damage, created from the byproducts of metabolism, including reactive species, spontaneous depurination of the DNA strands, and DNA single- and double-strands breaks from deoxyribose oxidation or replication fork collapse. Indeed, it has been proposed that much of the DNA repair machinery has evolved to content with DNA damage. Failure to repair these lesions leads to deleteriou mutations, genomic instability, cell death. In higher eukaryotes, the damage that occurs in genes responsible for DNA repair and/or cell cycle regulation can lead to threatening disease such as cancer. A major goal of this study is to identify the new DNA damage checkpoint protein, to find out the regulatory factor which regulates DNA repair genes and to investigate the DNA repair proteins against oxidative stress. in order to development of antimutagenic materials. The results that we found in this study are below. 1. We have found the potentially important DNA damage checkpoint protein, P3. P3 is phosphoylated and induced in response to DNA damage, and is involved in the sensing the DNA lesions. The downregulated P3 caused accumulation of DNA damage, decrease in double strand break repair and chromosomal instability. We believe P3 is an important novel DNA checkpoint protein. 2. We have found that Ras signal pathway contribute to the DNA repair regulation, and identified important transcription factors, which is involved in the transcriptional regulation of DNA repair genes. ERCC1 and Ku80, which are important DNA repair proteins, are up-regulated by Ras signal pathway, and Ap-1 involve in the Ras-mediated induction of ERCC1 expression. Bcl-2 and redox factor-1 suppress mismatch repair activity, and E2F1, one of the cell cycle related transcription factor, is contributed to Bcl-2-mediated suppression of hMSH2 expression. 3. We have found that two base excision repair proteins are important protective role agianst oxidative stress. hOGG1 and hMTH1 are repaired 8-oxoG in DNA and dNTP, respectively. We have found that these two proeins are able to protect cells against oxidative stress. 4. We have found that MT-III inhibits oxidative DNA mutation, even though hOGG1, which is main repair enzyme of oxidavite DNA lesions, is depleted. We believe that our results will be used to the development of antimutagenic drugs through further experiments, in order to prevent of senescence, cancer and neurodegerative disease.
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