DNAヒポメチル化により,突然変異率が高くなります
R Z Chen1, U Pettersson, C Beard
1Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
Nature
|September 17, 1998
まとめ
癌の特徴であるグローバルDNA低メチル化は,ゲノム不安定に関連しています. マウスにおけるDNAメチルトランスフェラーゼ (Dnmt1) 遺伝子の喪失は,突然変異率を劇的に増加させ,ゲノム安定性におけるDNAメチル化の役割を強調する.
科学分野:
- 遺伝学 遺伝学とは
- エピジェネティクス エピジェネティクス
- がん生物学 がん生物学
背景:
- 全球DNA低甲基化は腫瘍細胞で観察され,ゲノム不安定に関連しています.
- DNAメチレーションの欠陥は,結腸直腸腫瘍の細胞系不安定化に寄与する可能性があります.
- 低メチル化は,ICF症候群における染色体異常と,脱メチル化剤と関連している.
研究 の 目的:
- ゲノム安定性の維持におけるDNAメチル化の役割を調査する.
- 主要DNAメチルトランスフェラーゼ (Dnmt1) が欠けている細胞における突然変異率を決定する.
主な方法:
- Dnmt1遺伝子に対するヌリジゴスなネズミの胚性幹細胞を生成した.
- 内生性ヒポキサンチンフォスフォリボシルトランスフェラーゼ (Hprt) 遺伝子とウイルスチミジンキナーゼ (tk) トランスゲンの変異率を評価した.
- 遺伝子消去,ミトスの再結合,染色体喪失を含む突然変異の種類を分析した.
主要な成果:
- Dnmt1欠乏したネズミの胚性幹細胞は,HprtとTkのロシオの両方で,著しく高い突然変異率を示した.
- 遺伝子の消去が観察された主要な変異タイプでした.
- 複製によるミトスの再結合または染色体喪失は,Tk欠損の主要な原因でした.
結論:
- 哺乳類のDNAメチル化,特にDnmt1によるメチル化が,ゲノムの安定性を維持する上で重要な役割を果たしています.
- DNAメチル化の喪失は,変異率の増加と染色体不安定につながる可能性があります.
- これらの発見は,ゲノム全体の脱メチル化が発がんに寄与するという仮説を支持する.
関連する概念動画
Mismatch Repair
Overview
Epigenetic Regulation
Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
Overview of DNA Repair
In order to be passed through generations, genomic DNA must be undamaged and error-free. However, every day, DNA in a cell undergoes several thousand to a million damaging events by natural causes and external factors. Ionizing radiation such as UV rays, free radicals produced during cellular respiration, and hydrolytic damage from metabolic reactions can alter the structure of DNA. Damages caused include single-base alteration, base dimerization, chain breaks, and cross-linkage.
Chemically...
Chemically...
Epigenetic 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...
Mismatch Repair
Organisms are capable of detecting and fixing nucleotide mismatches that occur during DNA replication. This sophisticated process requires identifying the new strand and replacing the erroneous bases with correct nucleotides. Mismatch repair is coordinated by many proteins in both prokaryotes and eukaryotes.
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
Spontaneous and Induced Mutations
Spontaneous mutations arise infrequently during DNA replication due to errors in the process. A key factor behind these errors is tautomeric shifts in nitrogenous bases, where bases transition from keto to enol forms or amino to imino forms. This shift can alter base-pairing rules, leading to mutations. Additionally, reactive oxygen species (ROS) arising from aerobic metabolism can damage DNA, resulting in depurination (loss of a purine base) or depyrimidination (loss of a pyrimidine base).


