Deciphering pathways involved in topoisomerase II turnover

破译拓扑异构酶 II 周转涉及的途径

基本信息

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
项目类别：
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

项目摘要

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. .

项目概要 DNA 拓扑异构酶是一类可以通过瞬时特异性解决拓扑应力的酶。将链断裂引入 DNA 分子并使超螺旋 DNA 链旋转。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），将单链断裂引入 DNA 和 II 型拓扑异构酶（TOP2A、TOP2B 和 SPO11)，它将双链断裂 (DSB) 引入 DNA 中。本提案重点关注 II 类人类体细胞中的拓扑异构酶，即 TOP2A/2B。在裂解反应过程中，TOP2催化活性位点的酪氨酸与 DNA 主链并形成所谓的拓扑异构酶 II 裂解复合物 (TOP2cc)。正常情况下条件下，TOP2cc 会短暂形成并且无法检测到。然而，多种拓扑异构酶毒物，包括依托泊苷，已被开发并用作癌症治疗的化疗药物。从机制上讲，依托泊苷可稳定 TOP2cc，最终导致 DNA 链断裂并杀死肿瘤细胞。虽然包括我们在内的许多研究人员研究了 TOP2 诱导的 DNA 损伤以及如何修复它们通过不同的修复途径进行修复，该提案重点关注一个新概念，即细胞已经进化出不同的避免和限制 TOP2 诱导的 DNA 损伤的途径。在这个提案中，我们将机械地确定几个独特的 TOP2 调节因子如何共同作用以避免 DNA 损伤，从而促进细胞存活。这些研究的结果对于理解依托泊苷的治疗反应至关重要和其他抗癌剂。。