細胞タイプ固有の複製開始プログラムは,FRA3B脆弱部位の脆弱性を設定します
Anne Letessier1, Gaël A Millot, Stéphane Koundrioukoff
1Institut Curie, Centre de Recherche, 26 rue d'Ulm, 75248 Paris, France.
Nature
|January 25, 2011
まとめ
複製中に壊れやすい一般的な脆弱な部位は,がんと関連しています. この研究は,それらの不安定性は,がん研究に影響を与えるフォークスタリングではなく,DNA複製開始の欠如に起因することを明らかにしています.
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.
- がん研究 がん研究
背景:
- 常見の脆弱部位は,複製のストレスで壊れやすい染色体領域である.
- これらの部位は,DNAの損傷,染色体の再編成,がんの発症に関与しています.
- 以前の理論では,複製を妨げる二次構造に脆弱性があると考えられていた.
研究 の 目的:
- 一般的な脆弱部位の不安定性,特にFRA3B.の根本的なメカニズムを調査する.
- 脆弱性を複製フォークの減速と結びつける支配的な仮説に異議を唱えるために.
- 脆弱な部位の不安定性におけるDNA複製の開始とタイミングの役割を調査する.
主な方法:
- リンフォブラスト細胞および線維芽細胞におけるDNA複製開始パターンの分析.
- 一般的な脆弱性サイトのマッピングとその複製のタイミング.
- 異なる細胞タイプにおけるFRA3B脆弱性の比較研究.
主要な成果:
- FRA3Bの脆弱性は,複製フォークの減速によるものではなく,コア領域内のDNA複製開始イベントの欠如によるものです.
- リンパ芽細胞では観察されるが,線維芽細胞では観察されないこの初期化パターンは,複製フォークをより長い距離を移動させる.
- 隣接する領域における複製の起源は,S段階の後半に発火し,FRA3Bは不完全複製される.
- FRA3Bの不安定性は,細胞タイプ特異であり,異なる複製開始パターンと相関しています.
結論:
- 一般的な脆弱部位の不安定性は,遅発または複製の起源が存在しない地域から生じ,不完全な複製につながります.
- 原発発火の可塑性と複製のタイミングは,脆弱な部位の観察された組織特異性を説明します.
- 細胞型特異的なマッピングを考慮して,腫瘍に対する一般的な脆弱部位の貢献度の再評価が必要である.
関連する概念動画
01:02Long-patch Base Excision Repair
Since the discovery of the two BER pathways, there has been a debate about how a cell chooses one pathway over the other and the factors determining this selection. Numerous in vitro experiments have pointed out multiple determinants for the sub-pathway selection. These are:
02:10Translesion 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...
02:31Homologous Recombination
The basic reaction of homologous recombination (HR) involves two chromatids that contain DNA sequences sharing a significant stretch of identity. One of these sequences uses a strand from another as a template to synthesize DNA in an enzyme-catalyzed reaction. The final product is a novel amalgamation of the two substrates. To ensure an accurate recombination of sequences, HR is restricted to the S and G2 phases of the cell cycle. At these stages, the DNA has been replicated already and the...
02:37Restarting Stalled Replication Forks
DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart, a...
02:53Conservative Site-specific Recombination and Phase Variation
Because the DNA segments are cut and reorganized in a direction-specific manner, site-specific recombination has emerged as an efficient genetic engineering technique. Flippase and Cyclization recombinases or Flp and Cre, respectively, are two members of the tyrosine recombinase family derived from bacteriophages, that are used to mediate site-specific DNA insertions, deletions, and targeted expression of proteins in mammalian cell lines.
The recognition sites for Cre recombinase called LoxP...
The recognition sites for Cre recombinase called LoxP...
02:46Genome 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.