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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Published in:Molecular cell Vol. 82; no. 21; p. 4176
Main Authors: 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
Language:English
Published: United States 03.11.2022
Subjects:
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
Online Access:Get more information
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Summary: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.
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ISSN:1097-4164
1097-4164
DOI:10.1016/j.molcel.2022.09.009