老化中にタンパク質とタンパク質の相互作用を調節する保存されたNAD+結合ポケット
Jun Li1, Michael S Bonkowski1, Sébastien Moniot2
1Department of Genetics, Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA.
Science (New York, N.Y.)
|March 25, 2017
まとめ
ニコチナミドアデニンジヌクレオチド (NAD+) は,ヌディクスのホモロジードメインに結合し,DNA修復に不可欠なタンパク質の相互作用を調節する. NAD+の減少はDNAの修復を妨げますが,NAD+のレベルを回復するとこの減少が逆転します.
科学分野:
- 生物化学
- 分子生物学
- 老化に関する研究
背景:
- DNA修復の効率は 年齢とともに低下し 健康に悪影響を及ぼします
- タンパク質におけるヌディックスホモロジードメイン (NHD) の機能はほとんど知られていなかった.
- ニコチナミドアデニン・ディヌクレオチド (NAD+) 濃度は老化とともに低下する.
研究 の 目的:
- ヌディックスホモロジードメイン (NHD) の機能を解明する.
- DNA修復に関与するタンパク質とタンパク質の相互作用を調節するNAD+の役割を調査する.
- 老化,NAD+の減少,DNAの損傷の蓄積との関係を調査する.
主な方法:
- NAD+とNHDの結合を研究する生化学的試験.
- DBC1 と PARP1 を含むタンパク質相互作用の研究
- NAD+レベルがDNA修復に与える影響を評価する老齢マウスの実験.
主要な成果:
- ヌディックスホモロジードメイン (NHD) は,タンパク質の相互作用を調節するNAD+結合部位として識別される.
- DBC1へのNAD+結合 (乳がん1で消去される) は,PARP1 (ポリー- ADP- リボース) ポリメラーゼとの相互作用を抑制する.
- 老化しているマウスのNAD+レベルが低下すると,DBC1-PARP1の抑制が増加し,DNAの損傷が蓄積され,NAD+が回復すると逆戻りします.
結論:
- NAD+は NHD を通してタンパク質の相互作用を直接調節する.
- NAD+-DBC1-PARP1軸は,老化中のDNA修復の重要なレギュラーである.
- NAD+の豊富さを回復することは,年齢に関連するDNAの損傷,癌,放射線感受性を軽減する可能性を示している.
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