Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
12 03 2021
12 03 2021
Historique:
received:
12
05
2020
accepted:
11
02
2021
entrez:
13
3
2021
pubmed:
14
3
2021
medline:
2
4
2021
Statut:
epublish
Résumé
Minichromosome maintenance protein 10 (MCM10) is essential for eukaryotic DNA replication. Here, we describe compound heterozygous MCM10 variants in patients with distinctive, but overlapping, clinical phenotypes: natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus. To understand the mechanism of MCM10-associated disease, we modeled these variants in human cell lines. MCM10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere erosion. Our data suggest that loss of MCM10 function constrains telomerase activity by accumulating abnormal replication fork structures enriched with single-stranded DNA. Terminally-arrested replication forks in MCM10-deficient cells require endonucleolytic processing by MUS81, as MCM10:MUS81 double mutants display decreased viability and accelerated telomere shortening. We propose that these bi-allelic variants in MCM10 predispose specific cardiac and immune cell lineages to prematurely arrest during differentiation, causing the clinical phenotypes observed in both NKD and RCM patients.
Identifiants
pubmed: 33712616
doi: 10.1038/s41467-021-21878-x
pii: 10.1038/s41467-021-21878-x
pmc: PMC7955084
doi:
Substances chimiques
Cell Cycle Proteins
0
DNA-Binding Proteins
0
MCM10 protein, human
0
Endonucleases
EC 3.1.-
MUS81 protein, human
EC 3.1.-
Minichromosome Maintenance Proteins
EC 3.6.4.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1626Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM134681
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM083024
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA077598
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002494
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM074917
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009138
Pays : United States
Organisme : NIGMS NIH HHS
ID : R25 GM055336
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : R01 GM102413
Pays : United States
Organisme : Wellcome Trust
ID : WT 100127
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : R01 AI120989
Pays : United States
Organisme : Department of Health
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P30 CA016086
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM118047
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA190492
Pays : United States
Références
Front Immunol. 2017 May 01;8:449
pubmed: 28507545
Cell. 2011 Mar 4;144(5):646-74
pubmed: 21376230
J Biol Chem. 2018 Aug 17;293(33):12855-12861
pubmed: 29959228
Nat Rev Genet. 2018 Jan;19(1):51-62
pubmed: 29082913
Biochim Biophys Acta. 2011 Oct;1813(10):1777-83
pubmed: 21693137
Nature. 2015 Mar 26;519(7544):431-5
pubmed: 25739503
Genes Dev. 2006 Oct 15;20(20):2848-58
pubmed: 17015423
Cell Cycle. 2016 Aug 17;15(16):2183-2195
pubmed: 27327991
Proc Natl Acad Sci U S A. 2018 Sep 11;115(37):9276-9281
pubmed: 30150400
Nature. 2018 Mar 8;555(7695):265-268
pubmed: 29489749
Genes (Basel). 2018 Dec 24;10(1):
pubmed: 30586904
Immunol Rev. 2019 Jan;287(1):202-225
pubmed: 30565241
Ann N Y Acad Sci. 2007 Jun;1106:240-52
pubmed: 17303822
Cell. 2019 Oct 31;179(4):813-827
pubmed: 31675495
Nucleic Acids Res. 2014 Dec 16;42(22):e168
pubmed: 25300484
J Comput Biol. 2004;11(2-3):377-94
pubmed: 15285897
Bioinorg Chem Appl. 2016;2016:8206854
pubmed: 27524954
J Biol Chem. 2010 Mar 12;285(11):8352-62
pubmed: 20064936
J Cell Biol. 2013 Apr 29;201(3):373-83
pubmed: 23629964
Cell Rep. 2014 Apr 24;7(2):575-587
pubmed: 24726359
Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20240-5
pubmed: 19910535
Nucleic Acids Res. 2018 Jun 20;46(11):5634-5650
pubmed: 29741650
EMBO J. 2001 Dec 17;20(24):6958-68
pubmed: 11742973
Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10236-10241
pubmed: 16798881
Nat Genet. 2014 Aug;46(8):912-918
pubmed: 25017105
PLoS Genet. 2014 Apr 03;10(4):e1004251
pubmed: 24699519
Int J Oncol. 2010 Apr;36(4):929-40
pubmed: 20198338
Sci Rep. 2016 Sep 02;6:32510
pubmed: 27587191
Cell. 2018 Jan 25;172(3):439-453.e14
pubmed: 29290468
PLoS One. 2013 Jul 17;8(7):e69607
pubmed: 23874974
Cell Rep. 2016 Nov 1;17(6):1646-1656
pubmed: 27806302
Cell. 2009 Nov 13;139(4):719-30
pubmed: 19896182
Nucleic Acids Res. 2004 Jan 02;32(1):e3
pubmed: 14704360
Cell. 2009 Jul 10;138(1):90-103
pubmed: 19596237
Haematologica. 2008 Jun;93(6):943-4
pubmed: 18460650
Front Immunol. 2019 Jun 07;10:1150
pubmed: 31231365
Nat Commun. 2020 May 1;11(1):2147
pubmed: 32358495
Nat Commun. 2019 Feb 22;10(1):910
pubmed: 30796221
Am J Hum Genet. 2013 Mar 7;92(3):448-53
pubmed: 23453664
J Clin Invest. 2017 May 1;127(5):1991-2006
pubmed: 28414293
Mol Cell Biol. 2009 Feb;29(3):703-13
pubmed: 19015236
Elife. 2017 Nov 17;6:
pubmed: 29148972
Science. 2013 Oct 11;342(6155):239-42
pubmed: 24115439
Genes (Basel). 2017 Feb 17;8(2):
pubmed: 28218679
Elife. 2019 Jul 08;8:
pubmed: 31282859
EMBO J. 2006 Feb 8;25(3):565-74
pubmed: 16424902
PLoS Genet. 2010 Apr 22;6(4):e1000920
pubmed: 20421929
J Biol Chem. 2009 Sep 4;284(36):24662-72
pubmed: 19608746
Differentiation. 2018 Mar - Apr;100:31-36
pubmed: 29482077
Genes Dev. 2017 Feb 1;31(3):291-305
pubmed: 28270517
J Allergy Clin Immunol. 2015 Oct;136(4):1113-4
pubmed: 26025130
Cancer Discov. 2016 Jun;6(6):584-93
pubmed: 27029895
Open Biol. 2019 Aug 30;9(8):190117
pubmed: 31409229
J Crohns Colitis. 2020 Jan 1;14(1):142-147
pubmed: 31157858
Nucleic Acids Res. 1995 Sep 25;23(18):3794-5
pubmed: 7479015
Genome Res. 2011 Jun;21(6):936-9
pubmed: 20980556
Nat Protoc. 2013 Nov;8(11):2281-2308
pubmed: 24157548
Genome Med. 2019 Jul 25;11(1):46
pubmed: 31345272
Genes (Basel). 2019 Mar 19;10(3):
pubmed: 30893921
FEBS Lett. 2010 Sep 10;584(17):3831-8
pubmed: 20493861
Nat Cell Biol. 2019 Jan;21(1):94-101
pubmed: 30602768
Structure. 2008 Dec 10;16(12):1892-901
pubmed: 19081065
J Immunol. 2007 Apr 15;178(8):4947-55
pubmed: 17404276
Proc Natl Acad Sci U S A. 2019 Jan 15;116(3):798-803
pubmed: 30598452
J Immunol. 2019 Apr 1;202(7):1962-1969
pubmed: 30737273
Eur J Hum Genet. 2017 Jun;25(6):680-686
pubmed: 28327571
Trends Genet. 2018 Jul;34(7):518-531
pubmed: 29735283
J Clin Invest. 2012 Mar;122(3):821-32
pubmed: 22354167
Methods Mol Biol. 2019;1999:31-57
pubmed: 31127568
Elife. 2017 Sep 04;6:
pubmed: 28869037
Mol Biol Cell. 2006 Feb;17(2):955-65
pubmed: 16339074
J Clin Invest. 2020 Oct 1;130(10):5272-5286
pubmed: 32865517