TY - JOUR
T1 - Nopp140-mediated concentration of telomerase in Cajal bodies regulates telomere length
AU - Bizarro, Jonathan
AU - Bhardwaj, Amit
AU - Smith, Susan
AU - Thomas Meiera, U.
N1 - Funding Information:
We are grateful to John Reidhaar-Olson of the Einstein Gene Modification (formerly shRNA) Facility for generation and transduction of the Cas9 and NOLC1-sgRNA lentiviruses. We acknowledge for the referenced antibodies Maria Carmo-Fonseca, Phil Young, Francois Dragon, and Witek Filipowicz and Maria Vera for pGL3-UBC. The microscopes used are maintained by the Einstein Analytical Imaging Facility (AIF), which is partially supported by the NIH-funded Einstein Cancer Center (P30CA013330). We thank Maria Vera for her assistance with RNA-FISH and Rob Singer for use of his microscope. Leslie Gunther-Cummins (AIF) prepared and imaged the samples on an electron microscope supported by an NIH-funded Shared Instrumentation Grant (S10OD016214). This work was supported by grants from the National Institutes of Health, HL136662 (to U.T.M.) and CA116352 (to S.S.).
Publisher Copyright:
© 2019 Bizarro et al.
PY - 2019
Y1 - 2019
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.
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U2 - 10.1091/mbc.E19-08-0429
DO - 10.1091/mbc.E19-08-0429
M3 - Article
C2 - 31664887
AN - SCOPUS:85076450057
SN - 1059-1524
VL - 30
SP - 3136
EP - 3150
JO - Molecular biology of the cell
JF - Molecular biology of the cell
IS - 26
ER -