Publication Date:
2014-08-01
Description:
Haematopoietic stem cells (HSCs) self-renew for life, thereby making them one of the few blood cells that truly age. Paradoxically, although HSCs numerically expand with age, their functional activity declines over time, resulting in degraded blood production and impaired engraftment following transplantation. While many drivers of HSC ageing have been proposed, the reason why HSC function degrades with age remains unknown. Here we show that cycling old HSCs in mice have heightened levels of replication stress associated with cell cycle defects and chromosome gaps or breaks, which are due to decreased expression of mini-chromosome maintenance (MCM) helicase components and altered dynamics of DNA replication forks. Nonetheless, old HSCs survive replication unless confronted with a strong replication challenge, such as transplantation. Moreover, once old HSCs re-establish quiescence, residual replication stress on ribosomal DNA (rDNA) genes leads to the formation of nucleolar-associated gammaH2AX signals, which persist owing to ineffective H2AX dephosphorylation by mislocalized PP4c phosphatase rather than ongoing DNA damage. Persistent nucleolar gammaH2AX also acts as a histone modification marking the transcriptional silencing of rDNA genes and decreased ribosome biogenesis in quiescent old HSCs. Our results identify replication stress as a potent driver of functional decline in old HSCs, and highlight the MCM DNA helicase as a potential molecular target for rejuvenation therapies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456040/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456040/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Flach, Johanna -- Bakker, Sietske T -- Mohrin, Mary -- Conroy, Pauline C -- Pietras, Eric M -- Reynaud, Damien -- Alvarez, Silvia -- Diolaiti, Morgan E -- Ugarte, Fernando -- Forsberg, E Camilla -- Le Beau, Michelle M -- Stohr, Bradley A -- Mendez, Juan -- Morrison, Ciaran G -- Passegue, Emmanuelle -- F32 HL106989/HL/NHLBI NIH HHS/ -- R01 CA184014/CA/NCI NIH HHS/ -- R01 HL092471/HL/NHLBI NIH HHS/ -- R01 HL115158/HL/NHLBI NIH HHS/ -- T32 AI007334/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Aug 14;512(7513):198-202. doi: 10.1038/nature13619. Epub 2014 Jul 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Hem/Onc Division, University of California San Francisco, San Francisco, California 94143, USA [2] Institute of Experimental Cancer Research, Comprehensive Cancer Center, 89081 Ulm, Germany. ; The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Hem/Onc Division, University of California San Francisco, San Francisco, California 94143, USA. ; Center for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, Galway, Ireland. ; Spanish National Cancer Research Centre (CNIO), E-28049 Madrid, Spain. ; Department of Pathology, University of California San Francisco, San Francisco, California 94143, USA. ; Institute for the Biology of Stem Cells, Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California 95064, USA. ; Section of Hematology/Oncology and the Comprehensive Cancer Center, University of Chicago, Chicago, Illinois 60637, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25079315" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cell Aging/genetics/*physiology
;
Cell Proliferation
;
DNA Damage/genetics
;
DNA Replication/*physiology
;
DNA, Ribosomal/genetics
;
Female
;
Gene Expression Regulation
;
Hematopoietic Stem Cells/cytology/*pathology
;
Histones/genetics/metabolism
;
Male
;
Mice
;
Mice, Inbred C57BL
;
Minichromosome Maintenance Proteins/genetics
;
*Stress, Physiological
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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