A CONNECTION BETWEEN DNA REPAIR AND HIV RELATED IMMUNODEFICIENCY

DNA 修复与 HIV 相关免疫缺陷之间的联系

• 批准号: 6288742
• 负责人: VILHELM A. BOHR
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6288742
• 关键词: DNA directed DNA polymerase; DNA repair; HeLa cells; SCID mouse; T lymphocyte; calmodulin dependent protein kinase; enzyme inhibitors; fibroblasts; genetic transcription; human T cell lymphotropic virus type 1; human immunodeficiency virus 1; radiation genetics; recombinant DNA; transcription factor; ultraviolet radiation; virus genetics; virus protein

Summary of work: DNA repair enzymes are activated in response to DNA damage. Alterations in DNA repair enzyme function and thus the rate and extent of repair contribute to malignant transformation. Transcription of the gene encoding DNA polymerizing enzyme beta- polymerase, a repair enzyme, is shown to be inhibited by the human T-cell leukemia virus type I (HTLV-I) transactivator protein Tax. The resultant inhibition of DNA repair may lead to unrepaired chromosomal damage. Severe combined immunodeficient (SCID) mice have a mutation in the catalytic subunit of the DNA binding protein kinase that is involved in repair of double- strand breaks in DNA. To deter-mine if the protein is involved in repair of other types of breaks, we examined the ability of SCID cells to repair lesions introduced by ultraviolet light and X-ray irradiation. After ultraviolet irradiation, murine SCID fibroblast cell lines had 50% less repair of photoproducts in chromosomal DNA compared to a wildtype cell line, as shown by impaired cellular survival and decreased unscheduled DNA synthesis. SCID cells also had 50% less repair of ultraviolet damage in the transcribed dihydrofolate reductase and c-myc genes than wildtype cells. After gamma irradiation, SCID fibroblasts had 30% less repair of single-strand breaks than wildtype cells in the genes encoding immunoglobulin heavy and light chains.In all, we find a defect in gene repair and the processing of single stranded breaks in DNA in SCID cells. Thus, the DNA PKC enzyme appears to be involved not only in the processing of double stranded breaks as previously reported, but alos in the processing of single strand DNA breaks - HIV, Aids, immunodeficiency, DNA repair, DNA PK, double strand DNA breaks

工作总结：DNA修复酶在DNA损伤时被激活。DNA修复酶功能的改变以及修复的速率和程度有助于恶性转化。编码DNA聚合酶β-聚合酶（一种修复酶）的基因的转录显示被人T细胞白血病病毒I型（HTLV-I）反式激活蛋白Tax抑制。由此产生的DNA修复抑制可能导致未修复的染色体损伤。严重联合免疫缺陷（SCID）小鼠在DNA结合蛋白激酶的催化亚基中存在突变，该亚基参与DNA双链断裂的修复。为了确定该蛋白是否参与其他类型断裂的修复，我们检测了SCID细胞修复紫外线和X射线照射引起的损伤的能力。紫外线照射后，鼠SCID成纤维细胞系的染色体DNA中的光产物的修复比野生型细胞系少50%，如受损的细胞存活和减少的非程序性DNA合成所示。与野生型细胞相比，SCID细胞转录的二氢叶酸还原酶和c-myc基因对紫外线损伤的修复也减少了50%。γ射线照射后，SCID成纤维细胞编码免疫球蛋白重链和轻链的基因的单链断裂修复比野生型细胞少30%。总之，我们发现SCID细胞中基因修复和DNA单链断裂处理存在缺陷。因此，DNA PKC酶似乎不仅如先前报道的那样参与双链断裂的加工，而且还参与单链DNA断裂的加工- HIV、Aids、免疫缺陷、DNA修复、DNA PK、双链DNA断裂