Diminished apoptotic priming and ATM signalling confer a survival advantage onto aged haematopoietic stem cells in response to DNA damage
Open accessAbstract
Ageing of haematopoietic stem cells (HSCs) contributes to deficits in the aged haematopoietic system. HSC decline is driven in part by DNA damage accumulation; yet, how ageing impacts the acute DNA damage response (DDR) of HSCs is poorly understood. We show that old HSCs exhibit diminished ATM activity and attenuated DDR, leading to elevated clonal survival in response to a range of genotoxins that was underwritten by diminished apoptotic priming. Distinct HSC subsets exhibited ageing-dependent and subtype-dependent differences in apoptotic priming and survival in response to DNA damage. The defective DDR of old HSCs was non-cell autonomous, as ATM signalling and clonal survival in response to DNA damage could be restored to levels observed in young HSCs post-transplantated into young recipients. These data indicate that defective DDR and diminished apoptotic priming provide a selective advantage to old HSCs that may contribute to mutation accrual and disease predisposition.
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Cell death is also increased in ageing HSCs, and this is dependent on the DNA-damage signalling pathway ATM.
“Cell death is also increased in ageing HSCs, and this is dependent on the DNA-damage signalling pathway ATM96.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [96]
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References 61 · Cited by 60
- Authors
- Gutierrez-Martinez, P., Hogdal, L., Nagai, M., Kruta, M., Singh, R., Sarosiek, K., Nussenzweig, A., Beerman, I., Letai, A., & Rossi, D. J.
- Affiliations
- Harvard University (US)
- Boston Children's Hospital (US)
- National Institute on Aging (US)
- Corresponding author
- Letai, Anthony
- Rossi, Derrick J.
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2018-03-12
- Volume
- 20
- Issue
- 4
- Pages
- 413-421
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC6067675
- OpenAlex
- W2792863098
- Cited by
- 60
- References
- 61
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 9 · 2023: 11 · 2022: 4 · 2021: 9 · 2020: 9 · 2019: 8 · 2018: 1
- FWCI
- 4.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R00AG029760)
- National Heart, Lung, and Blood Institute (R01HL107630)
- National Cancer Institute (F31CA186301, P01CA066996, R00CA188679)
- National Institute of Diabetes and Digestive and Kidney Diseases (U01DK072473)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- hematopoietic stem cells, aging, DNA damage response, ATM signalling, genotoxins, non-cell-autonomous effects, bone marrow, HSC expansion
- MeSH terms
- Age Factors, Animals, Cells, Cultured, DNA Damage, DNA Repair, Hematopoietic Stem Cells, Male, Mice, Inbred C57BL, Time Factors, Signal Transduction, Cellular Senescence, Apoptosis, Hematopoietic Stem Cell Transplantation, Ataxia Telangiectasia Mutated Proteins
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