ヌクレオチド・アナログによって誘発された機能の増強は,ヒトDNAポリメラーゼイオタの誤りやすい性質を修正する
Amit Ketkar1, Maroof K Zafar, Surajit Banerjee
1Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205-7199, USA.
Journal of the American Chemical Society
|May 29, 2012
まとめ
人間のDNAポリメラーゼイオタ (hpol ι) は,DNA修復過程で誤りやすい. 改変された核酸であるN-MC-dATPは,酵素の活性部位を安定させ,不配列を防止することによってその精度を向上させます.
科学分野:
- 分子生物学は分子生物学である.
- バイオケミストリー バイオケミストリー
- 構造生物学 構造生物学とは
背景:
- YファミリーのDNAポリメラーゼは,DNA損傷耐性には極めて重要ですが,エラーが起こりやすい可能性があります.
- 人間のDNAポリメラーゼイオタ (hpol ι) は,ヒトのYファミリーのメンバーの中で最も誤りやすいです.
- hpol ιの忠誠性を理解することは,DNA修復機構の鍵です.
研究 の 目的:
- hpol ι.の精度を改善するための分子基盤を解明する.
- hpol ιの精度を向上させるための改変核酸N-MC-dATPの役割を調査する.
- N-MC-dATPが,hpol ι.におけるベースペアリングの好みをどのように変化させるかを決定する.
主な方法:
- hpol ιの3つの結晶構造をDNAと核酸の複合体で決定した.
- テンプレートdTを含むDNAと入力されたN-MC-dATPを含むHPOLIの三元複合体を分析した.
- N-MC-dATP,dATP,および南MC-dATPの結合と方向性を比較しました.
主要な成果:
- N-MC-dATPはアデニンリングの反指向を安定させ,変異性 dGTP:dT ペアリングを模倣します.
- 改変されていないdATPやSouth-MC-dATPとは異なり,N-MC-dATPは,Hoogsteen塩基対を形成するためにシングリコシル方向性を採用しません.
- N-MC-dATPの固定反コンフォーメーションは,Hoogsteenペアリングと比較して,より有利なベーススタッキングと触媒効率をもたらします.
結論:
- N-MC-dATPは,Hoogsteenのベースペアリングモードを防ぐことによって,hpol ιのエラーに弱い性質を修正します.
- N-MC-dATPのビサイクロ[3.1.0]ヘクサンの支架は,信頼性を高める構造的制約を課します.
- この研究は,ヒト転移DNAポリメラーゼの効率と忠誠度を調節するための新しい戦略を明らかにしています.
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関連する概念動画
Proofreading
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Errors During Replication are Corrected by the DNA Polymerase Enzyme
Errors During Replication are Corrected by the DNA Polymerase Enzyme
Proofreading
Overview
Genome Copying Errors
DNA replication is a well-evolved process that copies millions of base pairs with high fidelity during each cell division. Occasionally a wrong base or a long stretch of wrong bases may get added to the daughter strands. If the errors are left unchecked, cells might accumulate several mutations that might endanger their survival. Therefore, the copying errors are checked and repaired at three levels.
Translesion DNA Polymerases
Translesion (TLS) polymerases rescue stalled DNA polymerases at sites of damaged bases by replacing the replicative polymerase and installing a nucleotide across the damaged site. Doing so, TLS allows additional time for the cell to repair the damage before resuming regular DNA replication.
TLS polymerases are found in all three domains of life - archaea, bacteria, and eukaryotes. Of the different classes of TLS polymerases, members of the Y family are fitted with specialized structures that...
TLS polymerases are found in all three domains of life - archaea, bacteria, and eukaryotes. Of the different classes of TLS polymerases, members of the Y family are fitted with specialized structures that...
Mismatch Repair
Overview
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...
