Telomere length regulation and telomeric chromatin require the nonsense-mediated mRNA decay pathway
Telomere length regulation and telomeric chromatin require the nonsense-mediated mRNA decay pathway
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DOI：
10.1128/mcb.18.10.6121
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发表时间：
1998-10-01
影响因子：
5.3
通讯作者：
Berman, J
中科院分区：
文献类型：
--
作者：
Lew, JE;Enomoto, S;Berman, J
Rap1p定位因子4(RLF4)是在筛选影响端粒功能和改变端粒结合蛋白Rap1p定位的突变体时发现的一种酿酒酵母基因。在RLF4突变体中，端粒沉默减少，端粒DNA束变短，这表明RLF4对端粒染色质的建立和/或维持以及端粒长度的控制都是必需的。在这篇文章中，我们证明了RLF4与NMD2/UPF2等位基因，NMD2/UPF2是无意义介导的mRNA衰退(NMD)途径所必需的基因(Y.Cui，K.W.Hagan，S.Zhang，S.W.Peltz，Mel)。牢房。比奥尔。9：423-436,1995，和F.He和A.Jacobson，gene Dev.1995年9：437-454)。NMD途径需要Nmd2p/Rlf4p与另外两种蛋白质(Upf1p和Upf3p)一起，针对无意义的信息，通过外切核酸酶Xrn1p在细胞质中降解。UPF1和UPF3的缺失导致了端粒相关的缺陷，与rlf4突变引起的端粒相关缺陷类似，这意味着端粒功能需要的是NMD途径，而不是NMD无关的Nmd2p/Rlf4p功能。此外，端粒长度的调节需要Xrn1p而不是Rat1p，Rat1p是一种功能类似于Xrn1p的核外切核酸酶(A.W.Johnson，Mel.牢房。比奥尔。17：6122-6130,1997)。相反，在PAN2、PAN3或PAN2 PAN3菌株中没有观察到端粒相关的缺陷，这些缺陷存在于正常(而不是无意义的)mRNAs固有的死烯基化依赖的衰变。因此，NMD途径的缺失特异性地导致端粒的缺陷，表明正常细胞功能中对NMD途径的生理需求。我们提出了一个模型，其中NMD途径调节对端粒功能重要的特定mRNAs的水平。
Rap1p localization factor 4 (RLF4) is a Saccharomyces cerevisiae gene that was identified in a screen for mutants that affect telomere function and alter the localization of the telomere binding protein Rap1p. In rlf4 mutants, telomeric silencing is reduced and telomere DNA tracts are shorter, indicating that RLF4 is required for both the establishment and/or maintenance of telomeric chromatin and for the control of telomere length. In this paper, we demonstrate that RLF4 is allelic to NMD2/UPF2, a gene required for the nonsense-mediated mRNA decay (NMD) pathway (Y. Cui, K. W. Hagan, S. Zhang, and S. W Peltz, Mel. Cell. Biol. 9:423-436, 1995, and F. He and A. Jacobson, Genes Dev. 9:437-454, 1995). The NMD pathway, which requires Nmd2p/Rlf4p together with two other proteins, (Upf1p and Upf3p), targets nonsense messages for degradation in the cytoplasm by the exoribonuclease Xrn1p. Deletion of UPF1 and UPF3 caused telomere-associated defects like those caused by rlf4 mutations, implying that the NMD pathway, rather than an NMD-independent function of Nmd2p/Rlf4p, is required for telomere functions. In addition, telomere length regulation required Xrn1p but not Rat1p, a nuclear exoribonuclease with functional similarity to Xrn1p (A. W. Johnson, Mel. Cell. Biol. 17:6122-6130, 1997). In contrast, telomere-associated defects were not observed in pan2, pan3, or pan2 pan3 strains, which are defective in the intrinsic deadenylation-dependent decay of normal (as opposed to nonsense) mRNAs. Thus, loss of the NMD pathway specifically causes defects at telomeres, demonstrating a physiological requirement for the NMD pathway in normal cell functions. We propose a model in which the NMD pathway regulates the levels of specific mRNAs that are important for telomere functions.