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

Jonathan Bizarro, Amit Bhardwaj, Susan Smith, U. Thomas Meier

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)3136-3150
Number of pages15
JournalMolecular biology of the cell
Volume30
Issue number26
DOIs
StatePublished - Dec 15 2019

Fingerprint

Telomerase
Telomere
Dyskeratosis Congenita
Telomere Homeostasis
Small Nuclear Ribonucleoproteins
Telomere Shortening
Phosphoproteins
Body Size
Organelles
Proteins
RNA
Mutation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Nopp140-mediated concentration of telomerase in Cajal bodies regulates telomere length. / Bizarro, Jonathan; Bhardwaj, Amit; Smith, Susan; Meier, U. Thomas.

In: Molecular biology of the cell, Vol. 30, No. 26, 15.12.2019, p. 3136-3150.

Research output: Contribution to journalArticle

Bizarro, Jonathan ; Bhardwaj, Amit ; Smith, Susan ; Meier, U. Thomas. / Nopp140-mediated concentration of telomerase in Cajal bodies regulates telomere length. In: Molecular biology of the cell. 2019 ; Vol. 30, No. 26. pp. 3136-3150.
@article{cd984cf213124b8c8e29de0ee50cdd0e,
title = "Nopp140-mediated concentration of telomerase in Cajal bodies regulates telomere length",
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.",
author = "Jonathan Bizarro and Amit Bhardwaj and Susan Smith and Meier, {U. Thomas}",
year = "2019",
month = "12",
day = "15",
doi = "10.1091/mbc.E19-08-0429",
language = "English (US)",
volume = "30",
pages = "3136--3150",
journal = "Molecular Biology of the Cell",
issn = "1059-1524",
publisher = "American Society for Cell Biology",
number = "26",

}

TY - JOUR

T1 - Nopp140-mediated concentration of telomerase in Cajal bodies regulates telomere length

AU - Bizarro, Jonathan

AU - Bhardwaj, Amit

AU - Smith, Susan

AU - Meier, U. Thomas

PY - 2019/12/15

Y1 - 2019/12/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85076450057&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85076450057&partnerID=8YFLogxK

U2 - 10.1091/mbc.E19-08-0429

DO - 10.1091/mbc.E19-08-0429

M3 - Article

C2 - 31664887

AN - SCOPUS:85076450057

VL - 30

SP - 3136

EP - 3150

JO - Molecular Biology of the Cell

JF - Molecular Biology of the Cell

SN - 1059-1524

IS - 26

ER -