通过DNA聚合酶eta抑制皮肤癌的结构基础
Timothy D Silverstein1, Robert E Johnson, Rinku Jain
1Department of Structural and Chemical Biology, Mount Sinai School of Medicine, Box 1677, 1425 Madison Avenue, New York, New York 10029, USA.
Nature
|June 26, 2010
概括
DNA聚合酶eta (Poleta) 通过在一个开放的活性部位中容纳胺二次体,准确地复制紫外线损坏的DNA. 这种机制可以防止突变,降低皮肤癌风险.
科学领域:
- 分子生物学分子生物学
- 生物化学 生物化学
- 结构生物学 结构生物学
背景情况:
- DNA聚合酶eta (Poleta) 对于无错误的DNA复制至关重要,特别是通过紫外线诱导的病变.
- 波莱塔的缺陷导致皮肤色素变体 (XPV),这种情况会增加皮肤癌风险.
研究的目的:
- 阐明Poleta通过紫外线损坏的DNA复制的能力的结构和机制基础.
- 了解Poleta的活性部位是如何容纳和绕过胺二次体的.
主要方法:
- 在DNA (受损和未受损) 的三元复合体中Saccharomyces cerevisiae Poleta的X射线晶体学.
- 生物化学测试以评估聚合酶活性.
- 基因分析以确认功能角色.
主要成果:
- 晶体结构揭示了Poleta的开放活性点裂,与其他聚合酶不同.
- 该结构显示了氨酸-氨酸二聚体是如何安置在这个开放的裂.
- 特定的氨基酸相互作用 (Gln55,Arg73,Met74) 稳定了活性部位中的二元体.
结论:
- 波莱塔独特的活性部位结构能够通过UV诱导的胺二次体进行高效和准确的复制.
- 这种机制对于防止紫外线诱导的突变性和致癌性至关重要.
- 了解Poleta的功能为DNA修复和预防皮肤癌提供了洞察力.
相关概念视频
Nucleotide Excision Repair
Overview
Base Excision Repair
One of the common DNA damages is the chemical alteration of single bases by alkylation, oxidation, or deamination. The altered bases cause mispairing and strand breakage during replication. This type of damage causes minimal change to the DNA double helix structure and can be repaired by the base excision repair (BER) pathways. BER corrects damaged DNA sequences by removing the damaged base and restoring the original base sequence using the complementary strand as a template.
The first step of...
The first step of...
Long-patch Base Excision Repair
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:
Mutations
Mutations are changes in the sequence of DNA. These changes can occur spontaneously or they can be induced by exposure to environmental factors. Mutations can be characterized in a number of different ways: whether and how they alter the amino acid sequence of the protein, whether they occur over a small or large area of DNA, and whether they occur in somatic cells or germline cells.
Chromosomal Alterations Are Large-Scale Mutations
While point mutations are changes in a single nucleotide in...
Chromosomal Alterations Are Large-Scale Mutations
While point mutations are changes in a single nucleotide in...
Base Excision Repair
One of the common DNA damages is the chemical alteration of single bases by alkylation, oxidation, or deamination. The altered bases cause mispairing and strand breakage during replication. This type of damage causes minimal change to the DNA double helix structure and can be repaired by the base excision repair (BER) pathways. BER corrects damaged DNA sequences by removing the damaged base and restoring the original base sequence using the complementary strand as a template.
The first step of...
The first step of...
Nucleotide Excision Repair
DNA Distortion and Damage
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...


