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

Area of Science:

• Hematology
• Molecular Biology
• Cancer Research

Background:

• Stem cell division is implicated in cancer development through poorly understood pathways.
• Hematopoietic stem and progenitor cells (HSPCs) proliferate under stress, sometimes leading to DNA damage in hematopoietic stem cells (HSCs).
• It is unclear if this DNA damage affects progeny or triggers a DNA damage response (DDR).

Purpose of the Study:

• To investigate if DNA damage in activated HSCs persists in progeny and induces a DDR.
• To explore the mechanisms of DNA damage and repair during HSPC proliferation.
• To determine the role of PrimPol in HSC function and bone marrow reconstitution.

Main Methods:

• Simulated viral infection to induce HSPC proliferation in murine models.
• Transcriptomics, single-cell, and single-molecule assays on bone marrow cells.
• Competitive bone marrow transplantation assays.

Main Results:

• DNA damage induced by proliferation stimuli was confined to HSCs.
• Proliferating HSCs altered their DDR pathways in response to damage.
• Accelerated replication fork progression, mediated by PrimPol, occurred at the expense of fork reversal.
• PrimPol was essential for HSC amplification and bone marrow reconstitution.

Conclusions:

• DNA damage during stress-induced HSC proliferation is HSC-intrinsic.
• HSCs adapt their DDR to manage replication stress.
• Replication fork plasticity, regulated by PrimPol, is vital for HSC function and bone marrow regeneration.