スプライソームの破壊による直接的・間接的な影響は,無意味な媒介によるmRNA分解によって遺伝子調節を損なう.
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PubMedで要約を見る
まとめ
この要約は機械生成です。原因に関係なく,スプライソームの破壊は,無意味媒介 mRNA 崩壊 (NMD) 標的を大きく上調する. これはスプライソソームの機能不全と スプライソソーム症の細胞上の問題を関連付けています
科学分野
- 分子生物学
- 遺伝学
- 細胞生物学
背景
- spliceosomeによるpre-mRNAスプライシングは,ナンセンス媒介 mRNA崩壊 (NMD) の監視と結び付けられています.
- NMD経路は,早めの翻訳終結を検出するために,スプライソームによって貯蔵されたエクソン結合複合体 (EJC) に依存しています.
- 最近,スプライソーム成分が潜在的なNMD因子として特定されています.
研究 の 目的
- スプライソーム機能とNMDの関係を調べる
- NMDにおける直接的な役割を持つ特定のスプリセソーム成分を特定する.
- NMDによる細胞機能障害に寄与するかどうかを判断する.
主な方法
- スプライソーム成分が不足した細胞からのRNA-seqデータセットの分析.
- NMD標的のmRNAアイソフォームと新しいNMD基板の評価
- スプライセソーム阻害剤で治療された細胞または疾患に関連する変異を携えた細胞のトランスクリプトーム変異の検査.
主要な成果
- 触媒スプリセソームメンバーの枯渇は 自然なNMDの標的を上昇させた.
- AQR,SF3B1,SF3B4,CDC40は,NMDにおける潜在的な直接的な役割を示した.
- 新しいNMD基質の増加は,NMD抑制と相関しています.
- スプライソーム阻害と疾患関連変異は,これらのトランスクリプトーム変異を模倣した.
結論
- スプライソームの破壊は,原因に関係なく,NMDの標的を大きくアップレギュレーションします.
- このアップレギュレーションは,スプライソソモパシーで観察される細胞機能障害に寄与する可能性があります.
- この発見は,スプライソームの整合性とmRNAの監視の間の重要な関連性を強調しています.
関連する概念動画
The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
Before mRNAs are exported to the cytoplasm, it is crucial to check each mRNA for structural and functional integrity. Eukaryotic cells use several different mechanisms, collectively known as mRNA surveillance, to look for irregularities in mRNAs. Irregular or aberrant mRNA are rapidly degraded by various enzymes. If a defective mRNA escapes the surveillance, it would be translated into a protein which would either be non-functional or not function properly. One of the primary irregularities in...
Splicing is the process by which eukaryotic RNA is edited before its translation into protein. The RNA strand transcribed from eukaryotic DNA is called the primary transcript. The primary transcripts that become mRNAs are called precursor messenger RNAs (pre-mRNAs). Eukaryotic pre-mRNA contains alternating sequences of exons and introns. Exons are nucleotide sequences that code for proteins, whereas introns are the non-coding regions. In RNA splicing, introns are removed and exons are bonded...
The structure and stability of mRNA molecules regulates gene expression, as mRNAs are a key step in the pathway from gene to protein. In eukaryotes, the half-life of mRNA varies from a few minutes up to several days. mRNA stability is essential in growth and development. The absence of the proteins regulating its stability, such as tristetraprolin in mice, can cause systemic issues, including bone marrow overgrowth, inflammation, and autoimmunity.
Cis-acting Elements involved in mRNA stability
In eukaryotic cells, nascent mRNA transcripts need to undergo many post-transcriptional modifications to reach the cell cytoplasm and translate into functional proteins. For a long time, transcription and pre-mRNA processing were considered two independent events that occur sequentially in the cell. However, it has now been well established that transcription and pre-mRNA processing are two simultaneous processes that are precisely regulated inside the cell.
The chromatin structure, especially...
A gene is a stretch of DNA that serves as the blueprint for functional RNAs and proteins. Since DNA is comprised of nucleotides and proteins are comprised of amino acids, a mediator is required to convert the information encoded in DNA into proteins. This mediator is the messenger RNA (mRNA). mRNA copies the blueprint from DNA by a process called transcription. In eukaryotes, transcription occurs in the nucleus by complementary base-pairing with the DNA template. The mRNA is then...