DNMT1-DNA复合体的结构揭示了自身抑制在维护DNA甲基化中的作用
Jikui Song1, Olga Rechkoblit, Timothy H Bestor
1Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Science (New York, N.Y.)
|December 18, 2010
概括
基因组甲基转移酶-1 (DNMT1) 维持基因组甲基化. 结构研究揭示了DNMT1是如何形成的.
科学领域:
- 分子生物学分子生物学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 结构生物学 结构生物学
背景情况:
- 基因组甲基化模式对细胞功能至关重要,主要由DNA甲基转移酶-1 (DNMT1) 维持.
- 了解DNMT1的调节机制对于理解表观遗传稳定性和疾病发病机制至关重要.
研究的目的:
- 阐明DNMT1基质特异性和自身抑制的结构基础.
- 调查DNMT1如何区分非甲基化和半甲基化CpG位点,以确保准确的维护甲基化.
主要方法:
- 采用X射线晶体学来确定小鼠和人类DNMT1.1的结构.
- 解决了DNMT1复合体与含有非甲基化CpG位点的DNA结合的结构,揭示了CXXC,BAH1 / 2和甲基转移酶域的排列.
主要成果:
- 该CXXC域特别与非甲基化CpG二核酸结合.
- CXXC-BAH1链接器和BAH2循环将甲基转移酶域稳定在自抑制的构造中,防止进入非甲基化CpG位点.
- 这种结构安排确保DNMT1遮住非甲基化CpG位点,从而防止de novo甲基化并促进维护甲基化.
结论:
- DNMT1具有由其N端域 (CXXC和BAH1/2) 介导的内在自抑制机制.
- 这种机制通过防止未甲基化CpG位点的新甲基化来确保DNA甲基化维护的忠实性.
- 解决的结构为DNMT1活动的调节及其在维护表观遗传景观中的作用提供了关键的见解.
相关概念视频
01:46Epigenetic Regulation
Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
01:37Epigenetic Regulation
Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...
X-chromosome...
03:17Inheritance of Chromatin Structures
Epigenetics is the study of inherited changes in a cell's phenotype without changing the DNA sequences. It provides a form of memory for the differential gene expression pattern to maintain cell lineage, position-effect variegation, dosage compensation, and maintenance of chromatin structures such as telomeres and centromeres. For example, the structure and location of the centromere on chromosomes are epigenetically inherited. Its functionality is not dictated or ensured by the underlying DNA...
01:28Biosynthesis of Nucleic Acids
Nucleic acid biosynthesis is a fundamental biochemical process that produces the purine and pyrimidine nucleotides essential for DNA and RNA synthesis. This pathway maintains a balanced nucleotide pool, preventing imbalances that could jeopardize genetic integrity and cellular function. Given the crucial role of nucleotides, their synthesis is tightly regulated to ensure proper cellular homeostasis.Purine BiosynthesisThe biosynthesis of purine nucleotides begins with ribose-5-phosphate, a...
02:37Restarting Stalled Replication Forks
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, a...
02:36DNA Damage can Stall the Cell Cycle
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...