Resilient and resourceful: genome maintenance strategies in hematopoietic stem cells

Blood homeostasis is maintained by a rare population of quiescent hematopoietic stem cells (HSCs) that self-renew and differentiate to give rise to all lineages of mature blood cells. In contrast to most other blood cells, HSCs are preserved throughout life, and the maintenance of their genomic integrity is therefore paramount to ensure normal blood production and to prevent leukemic transformation. HSCs are also one of the few blood cells that truly age and exhibit severe functional decline in old organisms, resulting in impaired blood homeostasis and increased risk for hematologic malignancies. In this review, we present the strategies used by HSCs to cope with the many genotoxic insults that they commonly encounter. We briefly describe the DNA-damaging insults that can affect HSC function and the mechanisms that are used by HSCs to prevent, survive, and repair DNA lesions. We also discuss an apparent paradox in HSC biology, in which the genome maintenance strategies used by HSCs to protect their function in fact render them vulnerable to the acquisition of damaging genetic aberrations.