Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells
Open accessAbstract
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 γH2AX signals, which persist owing to ineffective H2AX dephosphorylation by mislocalized PP4c phosphatase rather than ongoing DNA damage. Persistent nucleolar γH2AX 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.
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DNA replication stress accumulation in HSCs from aged mice was associated with limited but detectable HSC senescence, unbalanced haematopoietic differentiation and myeloid skewing.
“accumulation of DNA replication stress in HSCs from aged mice was linked to limited yet detectable HSC senescence, unbalanced haematopoietic differentiation and myeloid skewing127.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [127]
Persistent H2AX phosphorylation was observed in the absence of ongoing DNA damage in quiescent old hematopoietic stem cells.
“Remarkably, persistent H2AX phosphorylation was recently observed in the absence of ongoing DNA damage in quiescent old hematopoietic stem cells (HSCs) (18).”
From Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability (2016) · cites this paper as [18]
Replication stress has been reported to cause persistent rDNA-associated γ-H2AX foci and reduced rRNA/ribosome biogenesis in quiescent old HSCs.
“it was recently reported that replication stress can result in the persistent formation of rDNA-associated γ-H2AX foci and a concomitant decrease in rRNA/ribosome biogenesis in quiescent old HSCs (18).”
From Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability (2016) · cites this paper as [18]
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- Authors
- Flach, J., Bakker, S. T., Mohrin, M., Conroy, P. C., Pietras, E. M., Reynaud, D., Alvarez, S., Diolaiti, M. E., Ugarte, F., Forsberg, E. C., Le Beau, M. M., Stohr, B. A., Méndez, J., Morrison, C. G., & Passegué, E.
- Affiliations
- University of California, San Francisco (US)
- Ollscoil na Gaillimhe – University of Galway (IE)
- University of California, Santa Cruz (US)
- Spanish National Cancer Research Centre (ES)
- ORCID
- Venue
- Nature
- Published
- 2014-07-30
- Volume
- 512
- Issue
- 7513
- Pages
- 198-202
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4456040
- OpenAlex
- W2085387059
- Cited by
- 650
- References
- 36
- Citations by year
- 2026: 39 · 2025: 37 · 2024: 44 · 2023: 56 · 2022: 44 · 2021: 74 · 2020: 64 · 2019: 61 · 2018: 57 · 2017: 43 · 2016: 68 · 2015: 53 · 2014: 9
- FWCI
- 40.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ARAN (University of Galway Research Repository) (Ollscoil na Gaillimhe – University of Galway) (acceptedVersion, cc-by-nc-nd)
- Arrow@dit (Dublin Institute of Technology) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- ARAN (University of Galway Research Repository) (Ollscoil na Gaillimhe – University of Galway) (submittedVersion, cc-by-nc-nd)
- eScholarship (California Digital Library) (submittedVersion)
- ARAN (University of Galway Research Repository) (Ollscoil na Gaillimhe – University of Galway) (submittedVersion, cc-by-nc)
- Research Repository UCD (University College Dublin) (cc-by-nc)
- Funders
- California Institute for Regenerative Medicine (RN2-00934)
- Science Foundation Ireland (10/IN.1/B2972)
- National Institutes of Health (NIH-R01)
- National Heart, Lung, and Blood Institute (R01HL115158, R01HL092471, F32HL106989)
- National Cancer Institute (R01CA184014)
- National Institute of Allergy and Infectious Diseases (T32AI007334)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- hematopoietic stem cells, aging, replication stress, MCM helicase, replication fork stalling, ribosomal DNA, ribosome biogenesis, stem cell quiescence, stem cell rejuvenation, DNA damage
- MeSH terms
- Animals, DNA Damage, DNA Replication, DNA, Ribosomal, Female, Gene Expression Regulation, Hematopoietic Stem Cells, Histones, Male, Mice, Inbred C57BL, Stress, Physiological, Cellular Senescence, Cell Proliferation, Mice, Minichromosome Maintenance Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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