Journal
NATURE CELL BIOLOGY
Volume 20, Issue 4, Pages 413-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41556-018-0054-y
Keywords
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Categories
Funding
- NIH
- National Cancer Institute
- Center for Cancer Research
- Alex Lemonade Stand Foundation Award
- NIH [F31CA186301, P01 CA066996, RO1HL107630, R00AG029760, UO1DK072473-01]
- Leukemia and Lymphoma Society [TRP6387-13]
- Leona M. and Harry B. Helmsley Charitable Trust
- New York Stem Cell Foundation
- Harvard Stem Cell Institute
- American Federation for Aging Research
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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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