Lin28-let-7経路におけるパールマン症候群外核酵素Dis3l2の役割について

Hao-Ming Chang¹, Robinson Triboulet, James E Thornton

¹Stem Cell Program, Boston Children's Hospital, Massachusetts 02115, USA.

Nature

|April 19, 2013

まとめ

多能性因子Lin28は,レット-7マイクロRNAの産生を抑制する. 研究者らは,Dis3l2を酵素分解性ウリジル化プレレット7として特定し,発育と癌にとって重要な新しいRNA分解経路を発見した.

科学分野:

分子生物学は分子生物学である.
発達生物学発達生物学について
癌生物学癌生物学について

背景:

Lin28は多能性因子であり,未微分化細胞におけるlet-7マイクロRNA (miRNA) 発現を阻害する.
Lin28は,Let-7 miRNAの生殖を阻害することによって,特定の癌の腫瘍遺伝子として作用します.
Lin28はウリジリルトランスファーゼをプリレット7RNAに誘導し,未知のRNaseによって分解する.

研究の目的:

ウリジル化プレレット-7の分解に起因する特定のRナゼを特定する.
RNAの分解信号としての3'オリゴウリジリレーションの役割を解明する.
この経路の発達と疾患における生理学的関連性を調査する.

主な方法:

精製されたタンパク質とRNAを用いた生化学的再構成アッセイ.
ネズミの胚性幹細胞におけるRNase候補のノックダウン.
pre-let-7 RNAの安定性と処理の分析.

主要な成果:

3'-5'エクソヌクレアースであるDis3l2は,uridylated pre-let-7を分解する酵素として特定されました.
3'オリゴウリジリレーションは,Dis3l2活性をインビトロで刺激することが示されました.
ネズミの胚性幹細胞におけるDis3l2のノックダウンは,pre-let-7安定化をもたらした.

結論:

Dis3l2は,uridylated pre-let-7の分解に起因する主要な核酵素である.
3'オリゴウリジリレーションは,Dis3l2.2の特定の崩壊信号として機能する.
この経路は,レット-7ミRNAのレベルを調節する上で重要であり,パールマン症候群とウィルムスの腫瘍に影響を及ぼします.

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