Deciphering pathways involved in topoisomerase II turnover

破译拓扑异构酶 II 周转涉及的途径

• 批准号: 10552113
• 负责人: Junjie Chen
• 金额: $ 50.3万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10552113
• 关键词: Active Sites; Agreement; Antineoplastic Agents; Biology; Bypass; CRISPR screen; Cell Cycle Inhibition; Cell Cycle Progression; Cell Death; Cell Proliferation; Cell Survival; Cells; Chromatin; Chromosome Segregation; Complex; DNA; DNA Adduction; DNA Adducts; DNA Damage; DNA Repair; DNA Topoisomerases; DNA lesion; DNA strand break; Ensure; Enzymes; Etoposide; Eukaryota; Excision; Fission Yeast; Genes; Genetic Transcription; Human; Knock-out; Lesion; Link; Literature; Mammalian Cell; Mediating; Pathway interactions; Poison; Process; Prokaryotic Cells; Proteins; Reaction; Regulation; Research Personnel; Resistance; Role; Rotation; SPO11 gene; Signal Transduction; Somatic Cell; Stress; Superhelical DNA; TOP1 gene; TOP2A gene; Testing; Therapeutic; Topoisomerase; Topoisomerase II; Topoisomerase III; Type I DNA Topoisomerases; Tyrosine; Vertebral column; Work; cancer therapy; experimental study; follow-up; neoplastic cell; protein protein interaction; repaired; response; treatment response; whole genome

PROJECT SUMMARY DNA topoisomerases are types of enzymes that can specifically resolve topological stresses by transiently introducing strand breaks into DNA molecules and enabling the rotation of the supercoiled DNA strand. Mammalian cells encode two types of topoisomerases: type I topoisomerases (TOP1, TOP1mt, TOP3A, and TOP3B), which introduce single strand breaks into DNA, and type II topoisomerases (TOP2A, TOP2B, and SPO11), which introduce double strand breaks (DSBs) into DNA. This proposal focuses on type II topoisomerases, i.e. TOP2A/2B, in human somatic cells. During cleavage reaction, the tyrosine in the catalytic active site of TOP2 is covalently linked to the DNA backbone and forms the so-called topoisomerase II cleavage complex (TOP2cc). Under normal conditions, TOP2cc forms transiently and is not detectable. However, a wide variety of topoisomerase poisons, including etoposide, have been developed and used as chemotherapeutic drugs for cancer treatment. Mechanistically, etoposide acts to stabilize TOP2cc, which eventually lead to DNA strand breaks and kill tumor cells. While many investigators including us investigated TOP2-induced DNA lesions and how they can be repaired by different repair pathways, this proposal focuses on a new concept that cells have evolved distinct pathways to avoid and limit DNA lesions induced by TOP2. In this proposal, we will determine mechanistically how several unique TOP2 regulators act together to avoid DNA damage and therefore promote cell survival. Results from these studies are critically important for the understanding of therapeutic response to etoposide and other anti-cancer agents. .

项目摘要 DNA拓扑异构酶是可以通过瞬时解决拓扑应力的酶类型 引入链分解成DNA分子并实现超螺旋DNA链的旋转。 哺乳动物细胞编码两种类型的拓扑异构酶：I型拓扑异构酶（TOP1，TOP1MT，TOP3A和 top3b），引入单链破裂成DNA，而II型拓扑异构酶（Top2a，top2b和 Spo11），将双链断裂（DSB）引入DNA中。该提案重点介绍II型 拓扑异构酶，即top2a/2b，在人类体细胞中。 在切割反应期间，TOP2的催化活性位点中的酪氨酸与 DNA主链并形成所谓的拓扑异构酶II裂解复合物（TOP2CC）。在正常情况下 条件，top2cc瞬时形成，无法检测到。但是，各种各样的拓扑异构酶毒物， 包括依托泊苷在内，已开发并用作癌症治疗的化学治疗药物。 从机械上讲，依托泊苷的作用是稳定top2cc，最终导致DNA链断裂并杀死肿瘤 细胞。 虽然包括美国在内的许多调查人员调查了TOP2诱导的DNA病变以及如何成为 该提案通过不同的维修途径修复，重点是一个新概念，即细胞已经发展出不同 避免和限制TOP2诱导的DNA病变的途径。在此提案中，我们将以机理的方式确定 几个独特的Top2调节剂如何共同起作用以避免DNA损伤，从而促进细胞存活。 这些研究的结果对于理解对依托泊苷的治疗反应至关重要 和其他抗癌代理商。 。