Hematopoietic stem cell quiescence promotes error prone DNA repair and mutagenesis

By Mary Mohrin, E. Bourke, David L. Alexander, M. Warr, K. Barry-Holson, M. L. Le Beau, C. Morrison, E. Passegué. Cell Stem Cell, 2010

604 citations recorded by the source corpus.

SUMMARY 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. Here, 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 pro-survival 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.

Subfields: Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/99b13a1702c75ee51ab0561374b195cf6ab9adc9

Citations in the corpus

• Programmed Cell Death in Animal Development and Disease (2011, neutral): “This differential resistance requires the ATM kinase, which induces cell-cycle arrest and DNA repair in HSPCs (Mohrin et al., 2010).”