Thymineless stress, DNA repair and recombination

无胸腺嘧啶应激、DNA 修复和重组

• 批准号: 7238685
• 负责人: MICHAEL D. WYATT
• 金额: $ 24.76万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7238685
• 关键词: Antineoplastic Agents; Apoptosis; Base Excision Repairs; Cause of Death; Cell Cycle Arrest; Cell Death; Class; Colon Carcinoma; Condition; Cytostatics; DNA; DNA Damage; DNA Ligases; DNA Repair; DNA strand break; Excision; Fluorouracil; Fluorouracil/Raltitrexed; Genetic Recombination; Genome Stability; Lead; Malnutrition; Nature; Normal Cell; Phase; Process; Signal Transduction; Site; Stress; Testing; Therapeutic Effect; Thymidine; Thymidylate Synthase; Thymidylate Synthase Inhibitor; Uracil; base; cancer cell; cancer therapy; chemotherapy; deprivation; recombinational repair; repaired; response; thymidine 5' -triphosphate; thymidylate; uracil-DNA glycosylase

DESCRIPTION (provided by applicant): The long-term objectives of this application are to better understand the DNA damage mechanisms that influence the response of normal cells and cancer cells to chemotherapy. Thymidylate deprivation is induced by inhibition of thymidylate synthase (TS) and is a therapeutic effect of several classes of antineoplastic drugs, such as 5-fluorouracil and raltitrexed (Tomudex). Inhibition of TS leads to loss of TTP necessary for replication. Thymidylate deprivation leads to cell death, unlike the cytostatic effects associated with other nutritional deficiencies. Despite decades of study, the precise mechanism by which TS inhibition causes death remains unclear. Some cellular responses to TS inhibition include an alteration in deoxynucleotide pools including an increase in dUTP levels, uracil incorporation into DNA, cell cycle arrest during S-phase, and induction of DNA strand breaks, likely at sites of replication. A key unanswered question remains "what is the specific nature of the damage during thymidylate deprivation that results in cell death?" The hypothesis to be tested in this project is that activation and progression of base excision repair (BER) under conditions of thymidylate deprivation lead to aberrant recombination and, eventually, apoptosis. The Specific Aims of this project are: Aim 1: To determine whether the initiation and progression of BER during thymidylate deprivation contributes to cell death. Aim 2: To determine the fate of BER intermediates during thymidylate deprivation. Aim 3: To determine whether chromosomal recombination is induced during thymidylate deprivation and to investigate the influence of BER on recombination occurring during thymidylate deprivation. Because BER and recombination normally contribute to genome stability, these questions have an added significance when current cancer therapies can themselves induce DNA damage.

描述（由申请人提供）：本申请的长期目标是更好地了解影响正常细胞和癌细胞对化疗反应的DNA损伤机制。胸苷酸剥夺是通过抑制胸苷酸合成酶 (TS) 引起的，并且是几类抗肿瘤药物（例如 5-氟尿嘧啶和雷替曲塞 (Tomudex)）的治疗作用。抑制 TS 会导致复制所需的 TTP 丢失。与其他营养缺乏相关的细胞抑制作用不同，胸苷酸缺乏会导致细胞死亡。尽管经过数十年的研究，TS 抑制导致死亡的确切机制仍不清楚。对 TS 抑制的一些细胞反应包括脱氧核苷酸池的改变，包括 dUTP 水平的增加、尿嘧啶掺入 DNA、S 期细胞周期停滞以及可能在复制位点诱导 DNA 链断裂。一个尚未解答的关键问题仍然是“导致细胞死亡的胸苷酸剥夺过程中损伤的具体性质是什么？”该项目要测试的假设是，在胸苷酸剥夺条件下，碱基切除修复（BER）的激活和进展会导致异常重组，并最终导致细胞凋亡。该项目的具体目标是： 目标 1：确定胸苷酸剥夺期间 BER 的启动和进展是否会导致细胞死亡。目标 2：确定胸苷酸剥夺期间 BER 中间体的命运。目标 3：确定胸苷酸剥夺期间是否诱导染色体重组，并研究 BER 对胸苷酸剥夺期间发生的重组的影响。由于 BER 和重组通常有助于基因组稳定性，因此当当前的癌症疗法本身会引起 DNA 损伤时，这些问题就显得尤为重要。