DNA修復と転写に欠陥のあるマウスの早期老化

Jan de Boer¹, Jaan Olle Andressoo, Jan de Wit

¹Medical Genetics Center, Department of Cell Biology and Genetics, Center for Biomedical Genetics, Erasmus University, 3000 DR Rotterdam, Netherlands.

Science (New York, N.Y.)

|April 16, 2002

まとめ

DNA損傷の蓄積は老化を促す可能性があります. 研究によると,トリコチオジストロフィーに関連したXPD遺伝子変異を持つマウスは,早期老化症状と寿命の短縮を示し,このDNA損傷仮説を支持しています.

科学分野:

遺伝学遺伝学とは
分子生物学は分子生物学である.
老化に関する研究

背景:

DNAダメージの蓄積は,老化プロセスの提案されたドライバーです.
XPD遺伝子は,DNA修復と転写に関与するDNAヘリコースをコードする.
XPDの変異は,ヒトの障害であるトリコチオジストロフィー (TTD) を引き起こします.

研究の目的:

マウスモデルを用いて,老化におけるDNA損傷の役割を調査する.
老化フェノタイプに対するXPD遺伝子変異の影響を調べる.
DNA修復の欠陥と加速された老化との関係を調査する.

主な方法:

XPD遺伝子に変異があるマウスを研究した.
TTDマウスにおける老化のフェノタイプを評価し,骨密度,寿命,および生育率を含む.
DNA修復欠陥を強化するためにXPAに追加の変異を導入した.
酸化性DNA損傷に対する細胞の相関感受性,加齢の加速.

主要な成果:

TTDマウスは,骨粗鬆症,キフォシス,骨硬化症,早期の灰色化,カシェキシア,不妊症,寿命の短縮など,多くの早期老化の兆候を示した.
XPDとXPAの合併変異を持つマウスは,著しく加速された老化現象型を示した.
加速された老化は,酸化性DNA損傷に対する細胞の感受性の増加と相関しています.

結論:

TTDマウスの修復されていないDNA損傷は,遺伝子の転写を損なうことで老化を起こす可能性が高い.
トランスクリプションが損なわれると,重要な遺伝子の機能不活性化とアポトーシスの増加が起こります.
この研究は,加齢によるDNA損傷理論を強く支持しています.

さらに関連する動画

15:40

Forward Genetic Approach to Uncover Stress Resistance Genes in Mice — A High-throughput Screen in ES Cells

Published on: November 11, 2015

07:46

Detection of DNA Double-Stranded Breaks in Mouse Oocytes

Published on: June 23, 2023

関連する概念動画

01:36

Mismatch Repair

Overview

01:08

Nucleotide Excision Repair

Overview

01:16

In-vitro Mutagenesis

To learn more about the function of a gene, researchers can observe what happens when the gene is inactivated or “knocked out,” by creating genetically engineered knockout animals. Knockout mice have been particularly useful as models for human diseases such as cancer, Parkinson’s disease, and diabetes.

02:25

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...

01:38

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...

01:20

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...

関連する実験動画