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Suppressors of mRNA Decapping Defects Restore Growth Without Major Effects on mRNA Decay Rates or Abundance.
GENETICS ( IF 3.3 ) Pub Date : 2020-09-30 , DOI: 10.1534/genetics.120.303641
Minseon Kim 1 , Ambro van Hoof 2
Affiliation  

Faithful degradation of mRNAs is a critical step in gene expression, and eukaryotes share a major conserved mRNA decay pathway. In this major pathway, the two rate determining steps in mRNA degradation are the initial gradual removal of the poly(A) tail, followed by removal of the cap structure. Removal of the cap structure is carried out by the decapping enzyme, containing the Dcp2 catalytic subunit. While the mechanism and regulation of mRNA decay is well-understood, the consequences of defects in mRNA degradation are less clear. Dcp2 has been reported as either essential or nonessential. Here we clarify that Dcp2 is not absolutely required for spore germination and extremely slow growth, but in practical terms it is impossible to continuously culture dcp2∆ under lab conditions without suppressors arising. We show that null mutations in at least three different genes are each sufficient to restore growth to a dcp2Δ, of which kap123Δ and tl(gag)gΔ appear the most specific. We show that kap123Δ and tl(gag)gΔ suppress dcp2 by mechanisms that are different from each other and from previously isolated dcp2 suppressors. The suppression mechanism for tL(GAG)G is determined by the unique GAG anticodon of this tRNA, and thus likely by translation of some CUC or CUU codons. Unlike previously reported suppressors of decapping defects, these suppressors do not detectably restore decapping or mRNA decay to normal rates, but instead allow survival while only modestly affecting RNA homeostasis. These results provide important new insight into the importance of decapping, resolve previously conflicting publications about the essentiality of DCP2, provide the first phenotype for a tl(gag)g mutant, and show that multiple distinct mechanisms can bypass Dcp2 requirement.

中文翻译:


mRNA 脱帽缺陷的抑制剂可恢复生长,而不会对 mRNA 衰减率或丰度产生重大影响。



mRNA 的忠实降解是基因表达的关键步骤,真核生物共享一个主要的保守 mRNA 降解途径。在此主要途径中,mRNA 降解的两个决定速率的步骤是最初逐渐去除 Poly(A) 尾,然后去除帽结构。帽结构的去除是通过含有 Dcp2 催化亚基的脱帽酶进行的。虽然 mRNA 降解的机制和调节已被充分了解,但 mRNA 降解缺陷的后果尚不清楚。据报道,Dcp2 要么是必需的,要么是非必需的。在这里我们澄清,Dcp2 并不是孢子萌发和极其缓慢的生长所绝对必需的,但实际上,在实验室条件下连续培养 dcp2Δ 而不产生抑制物是不可能的。我们表明,至少三个不同基因中的无效突变均足以恢复dcp2Δ的生长,其中kap123Δtl(gag)gΔ似乎最具特异性。我们发现kap123Δtl(gag)gΔ通过彼此不同且与之前分离的dcp2抑制剂不同的机制来抑制dcp2tL(GAG)G的抑制机制由该 tRNA 的独特 GAG 反密码子决定,因此可能是由某些 CUC 或 CUU 密码子的翻译决定的。与之前报道的脱盖缺陷抑制剂不同,这些抑制剂无法检测到将脱盖或 mRNA 衰减恢复到正常速率,而是允许存活,同时仅适度影响 RNA 稳态。 这些结果为了解开盖的重要性提供了重要的新见解,解决了先前关于DCP2重要性的冲突出版物,提供了tl(gag)g突变体的第一个表型,并表明多种不同的机制可以绕过 DCP2 的要求。
更新日期:2020-10-03
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