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PABPC1 与翻译起始复合物的相互作用对于 AUG 近端无意义突变的 NMD 抗性至关重要。

Interaction of PABPC1 with the translation initiation complex is critical to the NMD resistance of AUG-proximal nonsense mutations.

机构信息

Departamento de Genética, Instituto Nacional de Saúde Dr. Ricardo Jorge, 1649-016 Lisboa, Portugal.

出版信息

Nucleic Acids Res. 2012 Feb;40(3):1160-73. doi: 10.1093/nar/gkr820. Epub 2011 Oct 11.

DOI:10.1093/nar/gkr820
PMID:21989405
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3273812/
Abstract

Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that recognizes and rapidly degrades mRNAs containing premature termination codons (PTC). The strength of the NMD response appears to reflect multiple determinants on a target mRNA. We have previously reported that mRNAs containing PTCs in close proximity to the translation initiation codon (AUG-proximal PTCs) can substantially evade NMD. Here, we explore the mechanistic basis for this NMD resistance. We demonstrate that translation termination at an AUG-proximal PTC lacks the ribosome stalling that is evident in an NMD-sensitive PTC. This difference is associated with demonstrated interactions of the cytoplasmic poly(A)-binding protein 1, PABPC1, with the cap-binding complex subunit, eIF4G and the 40S recruitment factor eIF3 as well as the ribosome release factor, eRF3. These interactions, in combination, underlie critical 3'-5' linkage of translation initiation with efficient termination at the AUG-proximal PTC and contribute to an NMD-resistant PTC definition at an early phase of translation elongation.

摘要

无意义介导的 mRNA 降解（NMD）是一种监控途径，可识别并快速降解含有提前终止密码子（PTC）的 mRNA。NMD 反应的强度似乎反映了靶 mRNA 上的多个决定因素。我们之前曾报道过，靠近翻译起始密码子（AUG 近端 PTC）的 PTC 中包含的 mRNAs 可以显著逃避 NMD。在这里，我们探讨了这种 NMD 抗性的机制基础。我们证明，AUG 近端 PTC 处的翻译终止缺乏在 NMD 敏感的 PTC 中明显存在的核糖体停滞。这种差异与细胞质 poly(A)-结合蛋白 1（PABPC1）与帽结合复合物亚基 eIF4G 和 40S 募集因子 eIF3 以及核糖体释放因子 eRF3 的相互作用有关。这些相互作用结合在一起，为翻译起始与在 AUG 近端 PTC 处的有效终止之间的关键 3'-5' 连接奠定了基础，并有助于在翻译延伸的早期阶段对 NMD 抗性 PTC 进行定义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f325/3273812/cbe9d9850a78/gkr820f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f325/3273812/3e10d458fad2/gkr820f1a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f325/3273812/0d667bc47731/gkr820f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f325/3273812/525c52ef4656/gkr820f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f325/3273812/3f6be39bba70/gkr820f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f325/3273812/ccfaec29dd28/gkr820f5a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f325/3273812/cbe9d9850a78/gkr820f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f325/3273812/3e10d458fad2/gkr820f1a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f325/3273812/0d667bc47731/gkr820f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f325/3273812/525c52ef4656/gkr820f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f325/3273812/3f6be39bba70/gkr820f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f325/3273812/ccfaec29dd28/gkr820f5a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f325/3273812/cbe9d9850a78/gkr820f6.jpg

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