Department of Biosciences, University of Oslo, Oslo, Norway.
Biozentrum, University of Basel, Basel, Switzerland.
PLoS One. 2021 Jan 14;16(1):e0244505. doi: 10.1371/journal.pone.0244505. eCollection 2021.
Nonsense-mediated mRNA decay (NMD) controls eukaryotic mRNA quality, inducing the degradation of faulty transcripts. Key players in the NMD pathway were originally identified, through genetics, in Caenorhabditis elegans as smg (suppressor with morphological effect on genitalia) genes. Using forward genetics and fluorescence-based NMD reporters, we reexamined the genetic landscape underlying NMD. Employing a novel strategy for mapping sterile mutations, Het-Map, we identified clk-2, a conserved gene previously implicated in DNA damage signaling, as a player in the nematode NMD. We find that CLK-2 is expressed predominantly in the germline, highlighting the importance of auxiliary factors in tissue-specific mRNA decay. Importantly, the human counterpart of CLK-2/TEL2, TELO2, has been also implicated in the NMD, suggesting a conserved role of CLK-2/TEL2 proteins in mRNA surveillance. Recently, variants of TELO2 have been linked to an intellectual disability disorder, the You-Hoover-Fong syndrome, which could be related to its function in the NMD.
无意义介导的 mRNA 降解（NMD）控制真核 mRNA 的质量，诱导有缺陷的转录本降解。NMD 途径中的关键因子最初是通过遗传学在秀丽隐杆线虫中作为 smg（生殖器形态效应的抑制物）基因被鉴定出来的。我们使用正向遗传学和基于荧光的 NMD 报告物重新研究了 NMD 背后的遗传景观。我们采用一种新的用于映射不育突变的策略 Het-Map，鉴定出 clk-2，这是一个先前涉及 DNA 损伤信号的保守基因，是线虫 NMD 的参与者。我们发现 CLK-2 主要在生殖系中表达，突出了辅助因子在组织特异性 mRNA 降解中的重要性。重要的是，CLK-2/TEL2 的人类对应物 TELO2 也被牵连到 NMD 中，这表明 CLK-2/TEL2 蛋白在 mRNA 监测中具有保守作用。最近，TELO2 的变体与智力残疾障碍 You-Hoover-Fong 综合征有关，这可能与其在 NMD 中的功能有关。
