Full length RTEL1 is required for the elongation of the single-stranded telomeric overhang by telomerase.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
27 07 2020
27 07 2020
Historique:
accepted:
02
06
2020
revised:
29
05
2020
received:
29
12
2019
pubmed:
17
6
2020
medline:
17
9
2020
entrez:
17
6
2020
Statut:
ppublish
Résumé
Telomeres cap the ends of eukaryotic chromosomes and distinguish them from broken DNA ends to suppress DNA damage response, cell cycle arrest and genomic instability. Telomeres are elongated by telomerase to compensate for incomplete replication and nuclease degradation and to extend the proliferation potential of germ and stem cells and most cancers. However, telomeres in somatic cells gradually shorten with age, ultimately leading to cellular senescence. Hoyeraal-Hreidarsson syndrome (HHS) is characterized by accelerated telomere shortening and diverse symptoms including bone marrow failure, immunodeficiency, and neurodevelopmental defects. HHS is caused by germline mutations in telomerase subunits, factors essential for its biogenesis and recruitment to telomeres, and in the helicase RTEL1. While diverse phenotypes were associated with RTEL1 deficiency, the telomeric role of RTEL1 affected in HHS is yet unknown. Inducible ectopic expression of wild-type RTEL1 in patient fibroblasts rescued the cells, enabled telomerase-dependent telomere elongation and suppressed the abnormal cellular phenotypes, while silencing its expression resulted in gradual telomere shortening. Our observations reveal an essential role of the RTEL1 C-terminus in facilitating telomerase action at the telomeric 3' overhang. Thus, the common etiology for HHS is the compromised telomerase action, resulting in telomere shortening and reduced lifespan of telomerase positive cells.
Identifiants
pubmed: 32542379
pii: 5857711
doi: 10.1093/nar/gkaa503
pmc: PMC7367169
doi:
Substances chimiques
Telomerase
EC 2.7.7.49
RTEL1 protein, human
EC 3.6.1.-
DNA Helicases
EC 3.6.4.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7239-7251Subventions
Organisme : Worldwide Cancer Research
ID : 15-0338
Pays : United Kingdom
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
Références
Cytotechnology. 2004 Jun;45(1-2):33-8
pubmed: 19003241
Mol Biol Cell. 2012 Jul;23(14):2782-92
pubmed: 22593209
Mol Cell. 2015 Feb 19;57(4):622-635
pubmed: 25620558
Nucleic Acids Res. 2015 Feb 18;43(3):1834-47
pubmed: 25628358
Cell. 2009 Jul 10;138(1):90-103
pubmed: 19596237
Am J Hum Genet. 2013 Mar 7;92(3):448-53
pubmed: 23453664
Cell. 2012 May 11;149(4):795-806
pubmed: 22579284
Genes Dev. 2004 Jul 15;18(14):1649-54
pubmed: 15231715
PLoS One. 2009 May 22;4(5):e5666
pubmed: 19461895
Genome Biol. 2006;7 Suppl 1:S12.1-14
pubmed: 16925834
Nucleic Acids Res. 2018 May 18;46(9):4533-4545
pubmed: 29522136
Nature. 2019 Nov;575(7783):523-527
pubmed: 31723267
Hum Genet. 2013 Apr;132(4):473-80
pubmed: 23329068
Nature. 2003 Jun 26;423(6943):1013-8
pubmed: 12768206
J Biol Chem. 2013 Nov 15;288(46):33171-80
pubmed: 24097987
Hum Mutat. 2016 May;37(5):469-72
pubmed: 26847928
Hum Mol Genet. 2013 Aug 15;22(16):3239-49
pubmed: 23591994
Front Immunol. 2017 May 01;8:449
pubmed: 28507545
Blood Adv. 2018 Jan 04;2(1):36-48
pubmed: 29344583
Curr Biol. 2003 Sep 2;13(17):1549-56
pubmed: 12956959
EMBO Mol Med. 2019 Jul;11(7):e10201
pubmed: 31273937
Nucleic Acids Res. 2011 Mar;39(5):1647-55
pubmed: 21097466
Cell. 2004 Jun 25;117(7):873-86
pubmed: 15210109
Front Genet. 2015 Mar 24;6:91
pubmed: 25852739
Nature. 2012 Dec 13;492(7428):285-9
pubmed: 23103865
Nat Protoc. 2006;1(1):241-5
pubmed: 17406239
F1000Res. 2018 May 1;7:
pubmed: 29770205
Mol Cell. 2007 Jul 6;27(1):163-9
pubmed: 17612498
Genes Dev. 2014 Sep 1;28(17):1885-99
pubmed: 25128433
EMBO J. 2009 Apr 8;28(7):799-809
pubmed: 19214183
Br J Haematol. 2015 Aug;170(4):457-71
pubmed: 25940403
PLoS Genet. 2013 Aug;9(8):e1003695
pubmed: 24009516
Cell. 2018 Jan 25;172(3):439-453.e14
pubmed: 29290468
Hum Mol Genet. 2014 Jul 15;23(14):3629-40
pubmed: 24549038
Proc Natl Acad Sci U S A. 2013 Sep 3;110(36):E3408-16
pubmed: 23959892
Genes Dev. 2006 Oct 15;20(20):2848-58
pubmed: 17015423
Nat Biotechnol. 2009 Dec;27(12):1181-5
pubmed: 19935656
Methods Cell Biol. 2001;64:69-96
pubmed: 11070833
Science. 2013 Oct 11;342(6155):239-42
pubmed: 24115439
Blood Adv. 2016 Nov 22;1(1):36-46
pubmed: 29296694
Nucleic Acids Res. 2017 Feb 17;45(3):1219-1232
pubmed: 28180301
Cell Rep. 2019 Jun 18;27(12):3511-3521.e7
pubmed: 31216472
Mol Ther. 2000 Oct;2(4):404-14
pubmed: 11020357
J Cell Sci. 2004 Apr 15;117(Pt 10):1961-70
pubmed: 15039457
Mol Cell Biol. 2012 Jul;32(13):2384-95
pubmed: 22547674
Nat Rev Mol Cell Biol. 2017 Mar;18(3):175-186
pubmed: 28096526
Nature. 2019 Jan;565(7741):659-663
pubmed: 30675059
Annu Rev Genet. 2018 Nov 23;52:223-247
pubmed: 30208292
Science. 2006 May 12;312(5775):902-6
pubmed: 16690864