由状细胞主调节器POU2F3招募DNA依赖的协同激活剂的结构基础
Aktan Alpsoy1, Jonathan J Ipsaro2, Damianos Skopelitis1
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Cell reports
|November 19, 2025
概括
小细胞肺癌 (SCLC) 细胞依赖POU2F3及其协活性剂. 抑制POU2F3或OCA-T1导致瘤回归,揭示了SCLC中的可药物点.
科学领域:
- 分子生物学分子生物学
- 癌症研究 癌症研究
- 结构生物学是结构生物学.
背景情况:
- POU2F3转录因子识别了状细胞和特定的小细胞肺癌 (SCLC) 亚型.
- POU2F3被认为是无毒的,但它的功能取决于OCA-T1和OCA-T2联合激活剂.
研究的目的:
- 调查SCLC中POU2F3-OCA-T辅激剂依赖的结构基础和药物可用性.
- 在这种转录复合体内识别潜在的治疗点.
主要方法:
- 确定POU2F3结合OCA-T1/OCA-T2和DNA的晶体结构.
- 对POU2F3和OCA-T1进行深度突变扫描,以评估变异对瘤细胞适应性的影响.
主要成果:
- 对POU2F3或OCA-T1的急性抑制导致了状SCLC异种移植的回归.
- 晶体结构揭示了POU2F3,OCA-T1/OCA-T2和DNA之间的三方,DNA依赖的接口.
- 深度突变扫描确定了突变敏感的热点和瘤细胞适应性至关重要的受约束区域.
结论:
- POU2F3-OCA-T复合体将DNA识别与联合激活剂招募相结合.
- POU2F3-OCA-T在状细胞类癌症中代表了一个结构上可处理的漏洞,提供了一个潜在的治疗策略.
相关概念视频
Co-activators and Co-repressors
8.4K
Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
8.4K
Co-activators and Co-repressors
3.0K
3.0K
Master Transcription Regulators
7.7K
Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
7.7K
Master Transcription Regulators
2.7K
2.7K
Eukaryotic Transcription Activators
12.4K
Transcription activators are proteins that promote the transcription of genes from DNA to RNA. In most cases, these proteins contain two separate domains ‒ a domain that binds to DNA and a domain for activating transcription; however, in some cases, a single domain is responsible for both binding and activation of transcription, as seen in the glucocorticoid receptor and MyoD.
The binding domains are capable of recognizing and interacting with regulatory sequences on the DNA. These...
The binding domains are capable of recognizing and interacting with regulatory sequences on the DNA. These...
12.4K
RNA Polymerase II Accessory Proteins
10.7K
Proteins that regulate transcription can do so either via direct contact with RNA Polymerase or through indirect interactions facilitated by adaptors, mediators, histone-modifying proteins, and nucleosome remodelers. Direct interactions to activate transcription is seen in bacteria as well as in some eukaryotic genes. In these cases, upstream activation sequences are adjacent to the promoters, and the activator proteins interact directly with the transcriptional machinery. For example, in...
10.7K


