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Nat Cell Biol. 2018 Apr;20(4):413-421. doi: 10.1038/s41556-018-0054-y. Epub 2018 Mar 12.

Diminished apoptotic priming and ATM signalling confer a survival advantage onto aged haematopoietic stem cells in response to DNA damage.

Author information

1
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
2
Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
3
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
4
John B. Little Center for Radiation Sciences, Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
5
Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA.
6
Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD, USA.
7
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Anthony_Letai@dfci.harvard.edu.
8
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. Derrick.Rossi@childrens.harvard.edu.
9
Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. Derrick.Rossi@childrens.harvard.edu.
10
Department of Pediatrics, Harvard Medical School, Boston, MA, USA. Derrick.Rossi@childrens.harvard.edu.
11
Harvard Stem Cell Institute, Cambridge, MA, USA. Derrick.Rossi@childrens.harvard.edu.

Abstract

Ageing of haematopoietic stem cells (HSCs) contributes to deficits in the aged haematopoietic system. HSC decline is driven in part by DNA damage accumulation; yet, how ageing impacts the acute DNA damage response (DDR) of HSCs is poorly understood. We show that old HSCs exhibit diminished ATM activity and attenuated DDR, leading to elevated clonal survival in response to a range of genotoxins that was underwritten by diminished apoptotic priming. Distinct HSC subsets exhibited ageing-dependent and subtype-dependent differences in apoptotic priming and survival in response to DNA damage. The defective DDR of old HSCs was non-cell autonomous, as ATM signalling and clonal survival in response to DNA damage could be restored to levels observed in young HSCs post-transplantated into young recipients. These data indicate that defective DDR and diminished apoptotic priming provide a selective advantage to old HSCs that may contribute to mutation accrual and disease predisposition.

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