Peel Nina, Iyer Jyoti, Naik Anar, Dougherty Michael P, Decker Markus, O'Connell Kevin F
Department of Biology, The College of New Jersey, Ewing, NJ, United States of America.
Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 8 Center Drive, Bethesda, MD, United States of America.
PLoS Genet. 2017 Jan 19;13(1):e1006543. doi: 10.1371/journal.pgen.1006543. eCollection 2017 Jan.
In humans perturbations of centriole number are associated with tumorigenesis and microcephaly, therefore appropriate regulation of centriole duplication is critical. The C. elegans homolog of Plk4, ZYG-1, is required for centriole duplication, but our understanding of how ZYG-1 levels are regulated remains incomplete. We have identified the two PP1 orthologs, GSP-1 and GSP-2, and their regulators I-2SZY-2 and SDS-22 as key regulators of ZYG-1 protein levels. We find that down-regulation of PP1 activity either directly, or by mutation of szy-2 or sds-22 can rescue the loss of centriole duplication associated with a zyg-1 hypomorphic allele. Suppression is achieved through an increase in ZYG-1 levels, and our data indicate that PP1 normally regulates ZYG-1 through a post-translational mechanism. While moderate inhibition of PP1 activity can restore centriole duplication to a zyg-1 mutant, strong inhibition of PP1 in a wild-type background leads to centriole amplification via the production of more than one daughter centriole. Our results thus define a new pathway that limits the number of daughter centrioles produced each cycle.
在人类中，中心粒数量的扰动与肿瘤发生和小头畸形有关，因此，对中心粒复制进行适当调控至关重要。秀丽隐杆线虫中Plk4的同源物ZYG-1是中心粒复制所必需的，但我们对ZYG-1水平如何调控的理解仍不完整。我们鉴定出了两个PP1直系同源物GSP-1和GSP-2，以及它们的调节因子I-2SZY-2和SDS-22是ZYG-1蛋白水平的关键调节因子。我们发现，直接下调PP1活性，或通过szy-2或sds-22的突变，都可以挽救与zyg-1亚效等位基因相关的中心粒复制缺失。抑制作用是通过ZYG-1水平的增加来实现的，我们的数据表明PP1通常通过翻译后机制调节ZYG-1。虽然适度抑制PP1活性可以将中心粒复制恢复到zyg-1突变体，但在野生型背景下强烈抑制PP1会通过产生不止一个子中心粒导致中心粒扩增。因此，我们的结果定义了一条限制每个周期产生的子中心粒数量的新途径。
