DNA二重鎖によるATMの活性化は,Mre11-Rad50-Nbs1複合体を突破する
1Department of Molecular Genetics and Microbiology, Institute of Cellular and Molecular Biology, University of Texas at Austin, 1 University Station, A4800, Austin, TX 78712, USA.
Science (New York, N.Y.)
|March 26, 2005
まとめ
Mre11-Rad50-Nbs1 (MRN) 複合体は,DNAの二重鎖の断裂を感知し,アタクシア-テランジエクタシア変異 (ATM) キナーゼを勧誘する. MRNはDNAの末端を解き放ち,ATMを活性化し,DNA修復経路を誘発する.
科学分野:
- 分子生物学は分子生物学である.
- 細胞生物学 細胞生物学
- 遺伝学 遺伝学とは
背景:
- アタクシア-テランジエクタシア変異 (ATM) キナーゼは,哺乳類の細胞におけるDNA二重鎖断裂 (DSB) の重要なセンサーである.
- ATMの活性化は,下流の標的をリン酸化することによって,細胞サイクル停止,アポトーシス,DNA修復経路を開始します.
研究 の 目的:
- ATMの活性化におけるMre11-Rad50-Nbs1 (MRN) 複合体の役割を明らかにする.
- MRNがDSBのATMと相互作用するメカニズムを調査する.
主な方法:
- MRNとDNAの存在下でのATMの活性化を研究するためのインビトロ生化学測定法.
- p53やChk2.2のような下流ターゲットのATMオートフォスフォリレーションとフォスフォリレーションの分析.
主要な成果:
- MRN複合体は,DSBの直接センサーとして機能し,ATMを壊れたDNA部位に勧誘する.
- MRNは,ATMのオートフォスフォリレーションとは独立して,DNAの末端を解き放つことでATMの活性化を容易にします.
- 活性化されたATMリン酸塩は下流でp53とChk2を標的にし,機能的活性化を確認した.
結論:
- MRN複合体は,DNAの二重鎖の断裂を感知し,ATMを募集するために不可欠です.
- MRNによるDNA末端の解き放たれは,ATMの活性化にとって重要なステップであり,DNA損傷シグナリングにおける単一鎖DNAの役割を強調しています.
関連する概念動画
00:55DNA Helicases
DNA unwinding helicase enzymes are a type of motor protein. Motor proteins can translocate along filaments or polymers using energy generated from ATP hydrolysis. Helicases are involved in all the important cellular processes where DNA unwinding is required, such as DNA replication, repair, recombination, and transcription. They are present in all living organisms, but vary in their structure, function, and mechanism of action. For example, in prokaryotes, DnaB helicase binds and translocates...
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:
02:36DNA Damage can Stall the Cell Cycle
In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
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...
02:36DNA Damage Can Stall the Cell Cycle
In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...