Hematopoietic Stem Cell Quiescence Promotes Error-Prone DNA Repair and Mutagenesis
Open accessAbstract
Most adult stem cells, including hematopoietic stem cells (HSCs), are maintained in a quiescent or resting state in vivo. Quiescence is widely considered to be an essential protective mechanism for stem cells that minimizes endogenous stress caused by cellular respiration and DNA replication. We demonstrate that HSC quiescence can also have detrimental effects. We found that HSCs have unique cell-intrinsic mechanisms ensuring their survival in response to ionizing irradiation (IR), which include enhanced prosurvival gene expression and strong activation of p53-mediated DNA damage response. We show that quiescent and proliferating HSCs are equally radioprotected but use different types of DNA repair mechanisms. We describe how nonhomologous end joining (NHEJ)-mediated DNA repair in quiescent HSCs is associated with acquisition of genomic rearrangements, which can persist in vivo and contribute to hematopoietic abnormalities. Our results demonstrate that quiescence is a double-edged sword that renders HSCs intrinsically vulnerable to mutagenesis following DNA damage.
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Quiescent HSCs preferentially use NHEJ to repair DSBs.
“a recent study demonstrated that quiescent HSCs preferentially use NHEJ to repair DSBs126”
From Molecular regulation of stem cell quiescence (2013) · cites this paper as [126]
Homologous recombination occurs more predominantly in proliferating progenitor cells.
“homologous recombination has been reported to occur more predominantly in proliferating progenitor cells.”
From Molecular regulation of stem cell quiescence (2013) · cites this paper as [126]
Mouse HSCs forced to proliferate showed fewer mutational events after DNA-damaging radiation, suggesting that a break from quiescence enabling homologous recombination can help maintain stem cell genomic integrity.
“mouse HSCs that were forced to proliferate showed fewer mutational events after exposure to DNA-damaging radiation, suggesting that in certain instances a break from quiescence that enables engagement of the high-fidelity homologous recombination pathway can help to maintain stem cell genomic integrity56.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [56]
Quiescent HSCs and hair follicle stem cells rely more heavily on non-homologous end joining for double-strand break repair, while actively proliferating intestinal stem cells rely on homologous recombination.
“quiescent HSCs and hair follicle stem cells rely more heavily on non-homologous end joining for repair of double-strand breaks, while actively proliferating intestinal stem cells rely on the homologous recombination pathway56,187,188.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [56]
NHEJ is the only pathway not significantly differentially regulated between HSCs and progenitor cells, remaining mostly unchanged in both young and old mice.
“The only pathway that was not significantly differentially regulated in HSCs and progenitor cells was NHEJ, which remained mostly unchanged between HSCs and downstream progenitors in both young and old mice”
From Quiescent Hematopoietic Stem Cells Accumulate DNA Damage during Aging that Is Repaired upon Entry into Cell Cycle (2014) · cites this paper as Mohrin et al., 2010
Acute BM suppression occurs within days after exposure to IR, primarily as a result of induction of apoptosis in rapidly proliferating HPCs.
“Acute BM suppression occurs within days after exposure to ionizing radiation (IR), primarily as a result of induction of apoptosis in the rapidly proliferating hematopoietic progenitor cells (HPCs).3”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [3]
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References 34 · Cited by 599
- Authors
- Mohrin, M., Bourke, E., Alexander, D., Warr, M. R., Barry-Holson, K., Le Beau, M. M., 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)
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2010-08
- Volume
- 7
- Issue
- 2
- Pages
- 174-185
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC2924905
- OpenAlex
- W2157830903
- Cited by
- 599
- References
- 34
- Citations by year
- 2026: 17 · 2025: 20 · 2024: 30 · 2023: 36 · 2022: 28 · 2021: 46 · 2020: 48 · 2019: 37 · 2018: 35 · 2017: 37 · 2016: 54 · 2015: 46 · 2014: 41 · 2013: 40 · 2012: 43
- FWCI
- 16.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1117 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell stem cell (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)
- ARAN (University of Galway Research Repository) (Ollscoil na Gaillimhe – University of Galway) (submittedVersion, cc-by-nc-nd)
- 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
- National Cancer Institute (P01CA040046, P01-CA40046)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Keywords
- hematopoietic stem cells, stem cell quiescence, error-prone DNA repair, mutagenesis, ionizing radiation, radiation protection, non-homologous end joining, genome rearrangement
- MeSH terms
- Animals, Cell Survival, DNA Damage, DNA Repair, Hematopoietic Stem Cells, Mice, Inbred C57BL, Radiation Tolerance, Radiation, Ionizing, Recombination, Genetic, Signal Transduction, Tumor Suppressor Protein p53, Mutagenesis, Cell Death, Myeloid Progenitor Cells, Cell Proliferation, Mice
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