Quiescent Hematopoietic Stem Cells Accumulate DNA Damage during Aging that Is Repaired upon Entry into Cell Cycle

Hematopoietic stem cells (HSCs) maintain homeostasis and regenerate the blood system throughout life. It has been postulated that HSCs may be uniquely capable of preserving their genomic integrity in order to ensure lifelong function. To directly test this, we quantified DNA damage in HSCs and downstream progenitors from young and old mice, revealing that strand breaks significantly accrue in HSCs during aging. DNA damage accumulation in HSCs was associated with broad attenuation of DNA repair and response pathways that was dependent upon HSC quiescence. Accordingly, cycling fetal HSCs and adult HSCs driven into cycle upregulated these pathways leading to repair of strand breaks. Our results demonstrate that HSCs are not comprehensively geno-protected during aging. Rather, HSC quiescence and concomitant attenuation of DNA repair and response pathways underlies DNA damage accumulation in HSCs during aging. These results provide a potential mechanism through which premalignant mutations accrue in HSCs. [Display omitted] •HSCs are not uniquely geno-protected and accumulate DNA damage with age•DNA damage response and repair pathways are differentially regulated in HSCs•Attenuated damage repair and response in HSCs is dependent on quiescence but not age•HSCs G0 exit leads to upregulation of DDR and repair pathways and repair of damage Although stem cell quiescence has been thought to be cyto-protective, Beerman et al. find that strand breaks are present in quiescent HSCs and that attenuation of DNA response and repair pathways contributes to DNA damage accrual during aging.