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The DNA Replication Fork01:02

The DNA Replication Fork

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An organism’s genome needs to be duplicated in an efficient and error-free manner for its growth and survival. The replication fork is a Y-shaped active region where two strands of DNA are separated and replicated continuously. The coupling of DNA unzipping and complementary strand synthesis is a characteristic feature of a replication fork.   Organisms with small circular DNA, such as E. coli, often have a single origin of replication; therefore, they have only two replication...
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Replicative Cell Senescence02:15

Replicative Cell Senescence

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Replicative cell senescence is a property of cells that allows them to divide a finite number of times throughout the organism's lifespan while preventing excessive proliferation. Replicative senescence is associated with the gradual loss of the telomere — short, repetitive DNA sequences found at the end of the chromosomes. Telomeres are bound by a group of proteins to form a protective cap on the ends of chromosomes. Embryonic stem cells express telomerase — an enzyme that adds...
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Homologous Recombination02:31

Homologous Recombination

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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...
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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...
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Restarting Stalled Replication Forks02:37

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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,...
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複製のストレスにより,細胞の排除が促進される.

Vivek K Dwivedi1, Carlos Pardo-Pastor2, Rita Droste1

  • 1Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.

Nature
|May 6, 2021
PubMed
まとめ

細胞挤出は複製のストレスを通して細胞を排除し,動物間で保存されるプロセスです. このATR-CHK1とp53を伴うメカニズムは,哺乳類の腫瘍抑制剤として作用する.

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科学分野:

  • 細胞生物学
  • 発達生物学
  • 遺伝学

背景:

  • 細胞挤出は様々な生物で保存されている重要な細胞除去プロセスです.
  • 癌を含む上皮疾患に細胞挤出の調節不全が関与している.
  • 細胞の流出を駆動する正確な分子機構は完全に理解されていません.

研究 の 目的:

  • 細胞の流出に伴うメカニズムを調査する
  • ゲノム全体のスクリーンを用いて,細胞流出を制御する遺伝子を*Caenorhabditis elegans*で特定する.
  • 細胞の流出における複製ストレスの役割を決定する.

主な方法:

  • *Caenorhabditis elegans* 胚の全ゲノムRNA干渉スクリーンを実施した.
  • 細胞流出のダイナミクスを分析するために ライブイメージング実験を行った.
  • 哺乳類の上皮細胞における複製ストレスを引き起こすために,ヒドロキシ尿素を使用した.

主要な成果:

  • エクストルーションに不可欠なS相特有の機能を持つ細胞サイクル遺伝子を特定した.
  • エクストルージング細胞はATRとCHK1を通じて複製ストレスを経験し,それに反応することを実証した.
  • Sフェーズエントリーや複製ストレス反応を遮断すると,挤出が阻害されると示した.
  • 哺乳類の細胞における,ATR-CHK1とp53に依存する,ヒドロキシウレア誘発の複製ストレスによる誘発.

結論:

  • 複製ストレスによる細胞流出は動物種全体で保たれている.
  • このプロセスは細胞の除去のための原始的なメカニズムです.
  • 複製のストレスによって媒介される細胞挤出は,哺乳類における腫瘍抑制剤として機能する.