Defects in mtDNA replication challenge nuclear genome stability through nucleotide depletion and provide a unifying mechanism for mouse progerias.

Nature Metabolism
Riikka H HämäläinenAnu Suomalainen

Abstract

Mitochondrial DNA (mtDNA) mutagenesis and nuclear DNA repair defects are considered cellular mechanisms of ageing. mtDNA mutator mice with increased mtDNA mutagenesis show signs of premature ageing. However, why patients with mitochondrial diseases, or mice with other forms of mitochondrial dysfunction, do not age prematurely remains unknown. Here, we show that cells from mutator mice display challenged nuclear genome maintenance similar to that observed in progeric cells with defects in nuclear DNA repair. Cells from mutator mice show slow nuclear DNA replication fork progression, cell cycle stalling and chronic DNA replication stress, leading to double-strand DNA breaks in proliferating progenitor or stem cells. The underlying mechanism involves increased mtDNA replication frequency, sequestering of nucleotides to mitochondria, depletion of total cellular nucleotide pools, decreased deoxynucleoside 5'-triphosphate (dNTP) availability for nuclear genome replication and compromised nuclear genome maintenance. Our data indicate that defects in mtDNA replication can challenge nuclear genome stability. We suggest that defects in nuclear genome maintenance, particularly in the stem cell compartment, represent a unified mechanism fo...Continue Reading

References

Jan 1, 1988·Annual Review of Biochemistry·P Reichard
Apr 1, 1972·Journal of the American Geriatrics Society·D Harman
Jul 12, 1996·Cell·C BarlowA Wynshaw-Boris
Jun 19, 2003·The Journal of Clinical Investigation·Yutaka NishigakiMichio Hirano
Feb 27, 2004·The Journal of Biological Chemistry·James J PalacinoJie Shen
May 4, 2004·Experimental Cell Research·Mary Ann Handel
May 28, 2004·Nature·Aleksandra TrifunovicNils-Göran Larsson
Nov 23, 2005·Proceedings of the National Academy of Sciences of the United States of America·Henna TyynismaaAnu Suomalainen
Dec 8, 2005·Proceedings of the National Academy of Sciences of the United States of America·Aleksandra TrifunovicNils-Göran Larsson
Nov 2, 2006·Genome Biology·Anne E CarpenterDavid M Sabatini
Nov 8, 2008·Bioinformatics·Adi Laurentiu TarcaRoberto Romero
Apr 24, 2010·Human Molecular Genetics·Emil YlikallioAnu Suomalainen
Jun 22, 2010·Mutation Research·Chiara RampazzoVera Bianchi
Jan 5, 2012·Methods in Molecular Biology·Ramon MartíMichio Hirano
Oct 30, 2012·Bioinformatics·Alexander DobinThomas R Gingeras
Jun 12, 2013·Cell·Carlos López-OtínGuido Kroemer
Mar 1, 2014·Nature Cell Biology·Axel BehrensBjörn Schumacher
Jun 2, 2015·Cell Reports·Riikka H HämäläinenAnu Suomalainen
May 24, 2016·BioData Mining·Katherine IcaySampsa Hautaniemi
Aug 3, 2016·Disease Models & Mechanisms·Dido CarreroCarlos López-Otín
Oct 25, 2016·Nature Reviews. Disease Primers·Gráinne S GormanDouglass M Turnbull
Feb 2, 2017·Genes·Chen-Chun Pai, Stephen E Kearsey
May 10, 2017·Molecular and Cellular Biology·Keith WheatonSamuel Benchimol
Mar 9, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Cora Blázquez-BermejoYolanda Cámara
Oct 11, 2018·Biology Methods and Protocols·Juan Cruz LandoniAnu Suomalainen

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Citations

Jul 23, 2020·Nature Metabolism·Björn Schumacher, Jan Vijg
Oct 9, 2019·Nature Reviews. Molecular Cell Biology·Kim Baumann
Jul 1, 2020·International Journal of Molecular Sciences·Ekaterina ProshkinaAlexey Moskalev
Aug 9, 2020·Nature Structural & Molecular Biology·Yi FuAgnel Sfeir
Jan 3, 2020·The Journal of Clinical Investigation·Sofia KhanLaura L Elo
May 13, 2020·Nature Metabolism·Zheng WuGerald S Shadel
Oct 14, 2020·Nature Metabolism·Ruben BoonRaul Mostoslavsky
Feb 10, 2021·Journal of Cell Science·Lena Pernas
Dec 18, 2020·Frontiers in Cell and Developmental Biology·Tsu-Kung LinTzu-Jou Wang
Jun 4, 2020·Chemical Research in Toxicology·Linlin Zhao, Philip Sumberaz
Mar 21, 2021·Seminars in Cell & Developmental Biology·Jyung Mean Son, Changhan Lee
Apr 28, 2021·Nature Metabolism·Hans-Georg SprengerThomas Langer
May 22, 2021·Antioxidants & Redox Signaling·Gustavo CarvalhoPaulina H Wanrooij
Jun 6, 2021·Trends in Biochemical Sciences·Zheng WuGerald S Shadel
Jun 13, 2021·Development·Lluc MosteiroJelle van den Ameele

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Datasets Mentioned

BETA
SRP056999

Methods Mentioned

BETA
fluorescence-activated cell sorting
FACS
electrophoresis
genetic modification
Flow cytometry
PCR

Software Mentioned

SePIA
SPIA
ImageJ
QuantityOne
GraphPad Prism
Accuri C6 Analysis
STAR
Cuffdiff
Cufflinks
CellProfiler

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