Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis

Mary Mohrin; Emer Bourke; David Alexander; Matthew R. Warr; Keegan Barry-Holson; Michelle M. Le Beau; Ciaran G. Morrison; Emmanuelle Passegué

doi:10.1016/j.stem.2010.06.014

Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis

Mary Mohrin, Emer Bourke, David Alexander, Matthew R. Warr, Keegan Barry-Holson, Michelle M. Le Beau, Ciaran G. Morrison, Emmanuelle Passegué

Research output: Contribution to journal › Article › peer-review

526 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	174-185
Number of pages	12
Journal	Cell Stem Cell
Volume	7
Issue number	2
DOIs	https://doi.org/10.1016/j.stem.2010.06.014
State	Published - Aug 6 2010

Funding

We thank Drs. David Toczyski, Zhao-Qi Wang, and Martin Carroll for insights and suggestions, Elizabeth Davis for SKY analyses, Tara Rambaldo and Bill Hyun for management of the Flow Cytrometry core facility, Dr. Gordon Shore for anti-Bid antibody gift, Dr. William Weiss for Trp53 -/- mice, Dr. Andrew Leavitt for mobilization reagents, and all members of the Passegué laboratory for comments and discussion. M.M. is supported by a CIRM pre-doctoral training grant. This work was supported by a PHS P01 CA40046 to M.M.L., a Science Foundation Ireland PI award to C.G.M. and a CIRM New Investigator Award and Rita Allen Scholar Award to E.P.

Funders	Funder number
National Childhood Cancer Registry – National Cancer Institute	P01CA040046
National Childhood Cancer Registry – National Cancer Institute
California Institute for Regenerative Medicine	PHS P01 CA40046
California Institute for Regenerative Medicine

ASJC Scopus subject areas

Molecular Medicine
Genetics
Cell Biology

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abstract = "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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AU - Alexander, David

AU - Warr, Matthew R.

AU - Barry-Holson, Keegan

AU - Le Beau, Michelle M.

AU - Morrison, Ciaran G.

AU - Passegué, Emmanuelle

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Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis

Abstract

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