2008-08-012024-05-15https://scholars.lib.ntu.edu.tw/handle/123456789/661959摘要：為了避免在細胞分裂時錯誤的核&#33527;酸配對遺傳給下一代子細胞，同時為了維持DNA的完整性防止細胞不正常分裂，真核細胞發展出了縝密的偵測與修補系統，如果正常細胞DNA的突變嚴重至難以修補，甚至會啟動細胞凋亡機制來防止不正常細胞有進一步癌化的可能。當DNA受到紫外光、輻射線或化療藥物傷害時，會啟動偵測系統ATM/ATR、Chk1/Chk2蛋白質磷酸&#37238;對下游受質(如Cdc25, p53, and E2F)進行磷酸化作用，藉已停止或延長細胞週期運轉來等待DNA被修復或直接活化細胞凋亡機制。天生缺乏ATM基因表現的病人在臨床上顯示出神經系統衰退、免疫能力缺乏、對放射線或化療藥物極度敏感有發展成癌症的可能性，這些病人的生殖細胞因有缺陷的減數分裂重組反應因而導致不孕。在ATM基因剔除鼠的生殖細胞也看到了有缺陷的減數分裂細胞，伴隨著染色體斷裂的現象，同樣地，ATM基因剔除鼠也有精卵發育不全的現象。 我們先前的研究顯示人類p29蛋白屬於與染色質結合的蛋白質，細胞若轉殖p29的短鏈 siRNA會造成進行DNA複製的細胞減少，利用紫外光照射已轉殖p29短鏈 siRNA的細胞，結果會降低ATM與Chk1的磷酸化，推測缺少p29蛋白的細胞無法完成DNA複製的先期準備工作，因而減少ATM與Chk1的磷酸化，顯示p29與ATM的活化有關；我們與國家動物中心合作已建立mp29基因轉殖鼠，為了探討mp29基因轉殖鼠是否能補救ATM基因剔除鼠不孕的現象，我們將mp29基因轉殖鼠與ATM基因剔除鼠交配，觀察子代精虫發育情形並研究其可能機制。 <br> Abstract: Maintenance of genomic integrity and protection against harmful mutagenic effects of DNA damage rely on DNA damage response machinery, a complex network of signalling and effector pathways that coordinate cell cycle checkpoints with DNA repair and cell death mechanisms. In response to DNA lesions, the signal transducing kinases, ATM (ataxia telangiectasia-mutated), ATR(ataxia telangiectasia and Rad3-related), Chk1, and Chk2, phosphorylate downstream checkpoint effector proteins, such as Cdc25, p53, and E2F, to regulate cellular responses and ensure error-free DNA replication. In Atm-deficient mice, male and female gametogenesis is severely disrupted as early as leptonema of prophase I with significant chromosome fragmentation, and apoptotic degeneration, indicating recombination defects during meiosis. Our previous data demonstrated that the phosphorylation of ATM kinase at S1981 was suppressed in p29-depleted HeLa cells with UV irradiation (Cancer Res. 66, 8484-8491, 2006), suggesting a functional relevance between p29 and ATM. Recently, we generated mp29 transgenic mice and preliminary results showed that these mp29 overexpressed mice are less sensitive to UV irradiation compared with wild-type mice. Here, we would like to investigate whether mp29 overexpression could rescue the prophase-I arrest characteristic of Atm-deficient spermatocytes.DNA damage checkpointp29ATMtransgenespermatogenesisDNA damage checkpointp29ATMtransgenespermatogenesis