BRCA2ハプロイン不足とゲノム不安定を誘発する環境性および内生性毒素の一種

Shawn Lu Wen Tan¹, Saakshi Chadha¹, Yansheng Liu²

¹Medical Research Council Cancer Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK.

Cell

|June 3, 2017

まとめ

フォーマルデヒドのような環境毒素は BRCA2変異を有する個体において DNA複製を不安定化させることで癌を引き起こす可能性がありますこれは一般的なアルデヒドによる公衆衛生上のリスクを示しています

科学分野:

遺伝学
環境健康
分子生物学

背景:

BRCA2腫瘍抑制遺伝子の変異は,がんの感受性を高めます.
フォーマルデヒドは一般的な環境毒素であり,細胞代謝産物である.
BRCA2欠乏症はDNA修復メカニズム,特に同種再結合を損なう.

研究の目的:

ヘテロジゴスなBRCA2変異を有する細胞におけるDNA複製フォークに対するホルムアルデヒドの影響を調査する.
フォーマルデヒドがBRCA2発現と機能に影響を与えるメカニズムを解明する.
アルデヒド誘発のゲノム不安定性におけるRNA-DNAハイブリッド (R-ループ) の役割を調査する.

主な方法:

DNA複製フォークの安定性と染色体異常を評価するための細胞検査.
BRCA2タンパク質濃度を測定するプロテアソマル分解測定法
R-ループの役割を評価するためにリボヌクレアースH1を用いた実験.

主要な成果:

フォーマルデヒドはDNA複製フォークを停止し不安定化させ,BRCA2変異細胞の染色体異常を引き起こします.
フォーマルデヒドは,タンパク質分解によって選択的にBRCA2タンパク質を枯渇させる.
アセタルデヒドは同様の効果を誘発し,リボヌクレアースH1はこれらの問題を改善し,Rループの関与を示唆する.

結論:

低レベルのフォーマルデヒド暴露は,BRCA2ハプロイン欠乏症を誘発し,キャリアを癌に敏感にすることができます.
アルデヒド誘発のゲノム不安定は,DNA複製中に異常なRループによって発生する可能性があります.
環境および内生アルデヒドは,BRCA2変異媒体の公衆衛生上のリスクをもたらします.

キーワード:

BRCA2 について Rループスワット・MS アセタルデヒドアルデヒドフォーマルヒド誘発ハプロイン欠乏症タンパク質分解複製ストレス

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