Stress-triggered hematopoietic stem cell proliferation relies on PrimPol-mediated repriming

Stem cell division is linked to tumorigenesis by yet-elusive mechanisms. The hematopoietic system reacts to stress by triggering hematopoietic stem and progenitor cell (HSPC) proliferation, which can be accompanied by chromosomal breakage in activated hematopoietic stem cells (HSCs). However, whethe...

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Veröffentlicht in:Molecular cell Jg. 82; H. 21; S. 4176
Hauptverfasser: Jacobs, Kurt, Doerdelmann, Cyril, Krietsch, Jana, González-Acosta, Daniel, Mathis, Nicolas, Kushinsky, Saul, Guarino, Estrella, Gómez-Escolar, Carmen, Martinez, Dolores, Schmid, Jonas A, Leary, Peter J, Freire, Raimundo, Ramiro, Almudena R, Eischen, Christine M, Mendez, Juan, Lopes, Massimo
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 03.11.2022
Schlagworte:
Animals
Cell Proliferation
DNA Damage
DNA Replication
Hematopoiesis - genetics
Hematopoietic Stem Cells - physiology
Mice
DNA replication
Primpol
stem cell division
repriming
DNA damage response
bone marrow reconstitution
hematopoietic stem cells
replication fork plasticity
induced proliferation
ISSN:1097-4164, 1097-4164
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Abstract Stem cell division is linked to tumorigenesis by yet-elusive mechanisms. The hematopoietic system reacts to stress by triggering hematopoietic stem and progenitor cell (HSPC) proliferation, which can be accompanied by chromosomal breakage in activated hematopoietic stem cells (HSCs). However, whether these lesions persist in their downstream progeny and induce a canonical DNA damage response (DDR) remains unclear. Inducing HSPC proliferation by simulated viral infection, we report that the associated DNA damage is restricted to HSCs and that proliferating HSCs rewire their DDR upon endogenous and clastogen-induced damage. Combining transcriptomics, single-cell and single-molecule assays on murine bone marrow cells, we found accelerated fork progression in stimulated HSPCs, reflecting engagement of PrimPol-dependent repriming, at the expense of replication fork reversal. Ultimately, competitive bone marrow transplantation revealed the requirement of PrimPol for efficient HSC amplification and bone marrow reconstitution. Hence, fine-tuning replication fork plasticity is essential to support stem cell functionality upon proliferation stimuli.
AbstractList Stem cell division is linked to tumorigenesis by yet-elusive mechanisms. The hematopoietic system reacts to stress by triggering hematopoietic stem and progenitor cell (HSPC) proliferation, which can be accompanied by chromosomal breakage in activated hematopoietic stem cells (HSCs). However, whether these lesions persist in their downstream progeny and induce a canonical DNA damage response (DDR) remains unclear. Inducing HSPC proliferation by simulated viral infection, we report that the associated DNA damage is restricted to HSCs and that proliferating HSCs rewire their DDR upon endogenous and clastogen-induced damage. Combining transcriptomics, single-cell and single-molecule assays on murine bone marrow cells, we found accelerated fork progression in stimulated HSPCs, reflecting engagement of PrimPol-dependent repriming, at the expense of replication fork reversal. Ultimately, competitive bone marrow transplantation revealed the requirement of PrimPol for efficient HSC amplification and bone marrow reconstitution. Hence, fine-tuning replication fork plasticity is essential to support stem cell functionality upon proliferation stimuli.
Stem cell division is linked to tumorigenesis by yet-elusive mechanisms. The hematopoietic system reacts to stress by triggering hematopoietic stem and progenitor cell (HSPC) proliferation, which can be accompanied by chromosomal breakage in activated hematopoietic stem cells (HSCs). However, whether these lesions persist in their downstream progeny and induce a canonical DNA damage response (DDR) remains unclear. Inducing HSPC proliferation by simulated viral infection, we report that the associated DNA damage is restricted to HSCs and that proliferating HSCs rewire their DDR upon endogenous and clastogen-induced damage. Combining transcriptomics, single-cell and single-molecule assays on murine bone marrow cells, we found accelerated fork progression in stimulated HSPCs, reflecting engagement of PrimPol-dependent repriming, at the expense of replication fork reversal. Ultimately, competitive bone marrow transplantation revealed the requirement of PrimPol for efficient HSC amplification and bone marrow reconstitution. Hence, fine-tuning replication fork plasticity is essential to support stem cell functionality upon proliferation stimuli.Stem cell division is linked to tumorigenesis by yet-elusive mechanisms. The hematopoietic system reacts to stress by triggering hematopoietic stem and progenitor cell (HSPC) proliferation, which can be accompanied by chromosomal breakage in activated hematopoietic stem cells (HSCs). However, whether these lesions persist in their downstream progeny and induce a canonical DNA damage response (DDR) remains unclear. Inducing HSPC proliferation by simulated viral infection, we report that the associated DNA damage is restricted to HSCs and that proliferating HSCs rewire their DDR upon endogenous and clastogen-induced damage. Combining transcriptomics, single-cell and single-molecule assays on murine bone marrow cells, we found accelerated fork progression in stimulated HSPCs, reflecting engagement of PrimPol-dependent repriming, at the expense of replication fork reversal. Ultimately, competitive bone marrow transplantation revealed the requirement of PrimPol for efficient HSC amplification and bone marrow reconstitution. Hence, fine-tuning replication fork plasticity is essential to support stem cell functionality upon proliferation stimuli.
Author González-Acosta, Daniel
Krietsch, Jana
Kushinsky, Saul
Jacobs, Kurt
Doerdelmann, Cyril
Schmid, Jonas A
Eischen, Christine M
Mathis, Nicolas
Martinez, Dolores
Mendez, Juan
Freire, Raimundo
Lopes, Massimo
Guarino, Estrella
Gómez-Escolar, Carmen
Ramiro, Almudena R
Leary, Peter J
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  surname: González-Acosta
  fullname: González-Acosta, Daniel
  organization: Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland; DNA Replication Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain
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  organization: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
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  organization: Flow Cytometry Unit, Biotechnology Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain
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  organization: Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
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  givenname: Peter J
  surname: Leary
  fullname: Leary, Peter J
  organization: Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland; Functional Genomic Center Zurich, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
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  givenname: Raimundo
  surname: Freire
  fullname: Freire, Raimundo
  organization: Unidad de Investigación, Hospital Universitario de Canarias, Tenerife, Spain; Instituto de Tecnologías Biomédicas, Universidad de La Laguna, La Laguna, Spain; Universidad Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain
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  email: lopes@imcr.uzh.ch
  organization: Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. Electronic address: lopes@imcr.uzh.ch
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Issue 21
Keywords DNA replication
Primpol
stem cell division
repriming
DNA damage response
bone marrow reconstitution
hematopoietic stem cells
replication fork plasticity
induced proliferation
Language English
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Snippet Stem cell division is linked to tumorigenesis by yet-elusive mechanisms. The hematopoietic system reacts to stress by triggering hematopoietic stem and...
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SubjectTerms Animals
Cell Proliferation
DNA Damage
DNA Replication
Hematopoiesis - genetics
Hematopoietic Stem Cells - physiology
Mice
Title Stress-triggered hematopoietic stem cell proliferation relies on PrimPol-mediated repriming
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