Disease-associated human telomerase RNA variants show loss of function for telomere synthesis without dominant-negative interference.

Molecular and Cellular Biology
Timothy M ErringtonKathleen Collins

Abstract

Telomerase adds simple-sequence repeats to chromosome ends to offset the terminal sequence loss inherent in each cycle of genome replication. Inherited mutations in genes encoding subunits of the human telomerase holoenzyme give rise to disease phenotypes including hematopoietic failure and pulmonary fibrosis. Disease-associated variants of the human telomerase RNA are expressed in heterozygous combination with wild-type telomerase RNA. Here, we exploit a sensitized human primary cell assay system to investigate the biological function of disease-linked telomerase RNA variants and their impact on the function of coexpressed wild-type telomerase RNA. We find that telomerase RNA variants discovered in patients with dyskeratosis congenita or aplastic anemia show loss of function without any indication of dominant-negative impact on telomere maintenance by the coexpressed wild-type RNA. To reconcile this result with contradictory findings from reconstitution assays in vitro, we demonstrate that the lack of dominant-negative impact on telomere maintenance correlates with physiological assembly of active human telomerase holoenzyme ribonucleoproteins harboring monomers rather than higher-order multimers of telomerase RNA and telomera...Continue Reading

References

Sep 1, 1995·Science·J FengJ Yu
May 23, 1995·Proceedings of the National Academy of Sciences of the United States of America·K R Prowse, C W Greider
Oct 10, 1996·Experimental Cell Research·A G BodnarC P Chiu
Dec 22, 1998·Molecular and Cellular Biology·J R MitchellK Collins
Feb 7, 2001·Molecular and Cellular Biology·C K LaiK Collins
Jul 4, 2001·The EMBO Journal·C WenzJ Lingner
Aug 18, 2001·Molecular and Cellular Biology·T L BeattieL Harrington
Feb 19, 2002·Oncogene·Kathleen Collins, James R Mitchell
Mar 9, 2002·Molecular and Cellular Biology·April J LivengoodThomas R Cech
Jul 2, 2002·Lancet·Tom VulliamyPhilip J Mason
Sep 5, 2002·Microbiology and Molecular Biology Reviews : MMBR·Yu-Sheng CongJerry W Shay
Oct 5, 2002·Nucleic Acids Research·Francis Lim, David S Peabody
May 29, 2003·Molecular Cell·Dragony Fu, Kathleen Collins
Jun 13, 2003·Lancet·David B WilsonMonica Bessler
Jun 25, 2003·Molecular Cell·Cary K LaiKathleen Collins
Sep 19, 2003·Molecular Biology of the Cell·Tracy M BryanThomas R Cech
Sep 27, 2003·Lancet·Judy M Y Wong, Kathleen Collins
Jan 28, 2004·Cell·Thomas R Cech
May 8, 2004·Genes & Development·Keren L Witkin, Kathleen Collins
May 19, 2005·Molecular and Cellular Biology·Doreen D Cunningham, Kathleen Collins
Jan 21, 2006·The EMBO Journal·Gaël Cristofari, Joachim Lingner
May 23, 2006·Current Opinion in Structural Biology·Carla A Theimer, Juli Feigon
Jun 3, 2006·Chromosoma·Nele Hug, Joachim Lingner
Jun 8, 2006·Annual Review of Biochemistry·Chantal Autexier, Neal F Lue
Jul 11, 2006·Nature Reviews. Molecular Cell Biology·Kathleen Collins
Oct 4, 2006·Genes & Development·Judy M Y Wong, Kathleen Collins
Oct 7, 2006·Nature Medicine·Elizabeth H BlackburnJack W Szostak
Mar 27, 2007·Cold Spring Harbor Symposia on Quantitative Biology·S Li, E H Blackburn
Mar 27, 2007·Cold Spring Harbor Symposia on Quantitative Biology·C W Greider
Jun 22, 2007·Nature·Ramiro E Verdun, Jan Karlseder
Sep 22, 2007·Nature Reviews. Molecular Cell Biology·Eric Gilson, Vincent Géli

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Citations

Mar 12, 2013·Nature Structural & Molecular Biology·Anselm SauerwaldDaniela Rhodes
Dec 22, 2009·The Journal of Biological Chemistry·Aaron R Robart, Kathleen Collins
May 13, 2010·Nucleic Acids Research·Haley D M WyattTara L Beattie
Aug 1, 2013·Nucleic Acids Research·Arthur J ZaugThomas R Cech
Mar 31, 2010·Molecular and Cellular Biology·Emily D Egan, Kathleen Collins
Aug 6, 2011·Current Opinion in Chemical Biology·Kathleen Collins
Jul 13, 2011·Mutation Research·Nya D Nelson, Alison A Bertuch
Mar 17, 2017·Annual Review of Biophysics·Henry ChanJuli Feigon
Sep 22, 2020·RNA Biology·Mauno Vihinen
Nov 14, 2020·The Journal of Biological Chemistry·Sherilyn Grill, Jayakrishnan Nandakumar
Jan 23, 2021·The Journal of Biological Chemistry·Sherilyn Grill, Jayakrishnan Nandakumar

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