Nopp140-mediated concentration of telomerase in Cajal bodies regulates telomere length

Mol Biol Cell. 2019 Dec 15;30(26):3136-3150. doi: 10.1091/mbc.E19-08-0429. Epub 2019 Oct 30.

Abstract

Cajal bodies (CBs) are nuclear organelles concentrating two kinds of RNA--protein complexes (RNPs), spliceosomal small nuclear (sn), and small CB-specific (sca)RNPs. Whereas the CB marker protein coilin is responsible for retaining snRNPs, the tether for scaRNPs is not known. Here we show that Nopp140, an intrinsically disordered CB phosphoprotein, is required to recruit and retain all scaRNPs in CBs. Knockdown (KD) of Nopp140 releases all scaRNPs leading to an unprecedented reduction in size of CB granules, hallmarks of CB ultrastructure. The CB-localizing protein WDR79 (aka TCAB1), which is mutated in the inherited bone marrow failure syndrome dyskeratosis congenita, is a specific component of all scaRNPs, including telomerase. Whereas mislocalization of telomerase by mutation of WDR79 leads to critically shortened telomeres, mislocalization of telomerase by Nopp140 KD leads to gradual extension of telomeres. Our studies suggest that the dynamic distribution of telomerase between CBs and nucleoplasm uniquely impacts telomere length maintenance and identify Nopp140 as a novel player in telomere biology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line, Tumor
  • Coiled Bodies / metabolism*
  • Dyskeratosis Congenita / genetics
  • HeLa Cells
  • Humans
  • Molecular Chaperones / genetics*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Telomerase / genetics
  • Telomerase / metabolism*
  • Telomere / physiology*
  • Telomere Homeostasis / physiology*

Substances

  • Molecular Chaperones
  • NOLC1 protein, human
  • Nuclear Proteins
  • Phosphoproteins
  • RNA, Small Interfering
  • Telomerase
  • WRAP53 protein, human