致病性BRCA1突变破坏了BARD1的菌控制.
Ayan Bhattacharjee1, Gregory R Bowman1
1Departments of Biochemistry & Biophysics and Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
The journal of physical chemistry. B
|July 29, 2025
概括
致病性BRCA1突变通过改变BARD1结合和蛋白质活性来破坏癌细胞调节. 了解这些生物物理变化为遗传性乳腺癌和卵巢癌的新疗法设计提供了信息.
科学领域:
- 生物物理学的生物物理.
- 分子生物学分子生物学
- 计算生物学 计算生物学
背景情况:
- 在BRCA1的致病突变与遗传性乳腺癌和卵巢癌有关.
- 这些突变破坏BRCA1功能并导致瘤发生的确切机制尚不清楚.
- 通过与BARD1.1结合来调节BRCA1的E3酶活性.
研究的目的:
- 为了研究BARD1结合激活BRCA1 E3结合酶活性的全性机制.
- 为了阐明BRCA1中的病原性突变如何扰乱这些激活机制.
- 为设计针对BRCA1.1的治疗方法提供机制性见解.
主要方法:
- 原子学分子动力学模拟.
- 马尔科夫状态建模.
- 分析BARD1结合部位与E2接口之间的全结合.
主要成果:
- BARD1结合选择并稳定BRCA1.1的活性构造状态.
- BARD1的结合部位 (螺旋捆) 与E2接口结合.
- 病原性突变会破坏这些活跃状态的稳定,而过度活跃的突变会增加它们的可能性.
结论:
- 通过BARD1介导的BRCA1激活是一种形状选择过程.
- 致病性BRCA1突变通过异质地破坏这些活性构造来发挥其作用.
- 这些发现为开发用于恢复BRCA1功能的小分子疗法提供了机制基础.
更多相关视频
相关概念视频
Restarting Stalled Replication Forks
5.9K
DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
5.9K
DNA Damage can Stall the Cell Cycle
9.3K
In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
9.3K
The Intrinsic Apoptotic Pathway
6.9K
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
6.9K
mTOR Signaling and Cancer Progression
3.9K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
3.9K
Abnormal Proliferation
4.6K
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.6K
Long-patch Base Excision Repair
7.2K
Since the discovery of the two BER pathways, there has been a debate about how a cell chooses one pathway over the other and the factors determining this selection. Numerous in vitro experiments have pointed out multiple determinants for the sub-pathway selection. These are:
7.2K


