Oxidative Stress, Bone Marrow Failure, and Genome Instability in Hematopoietic Stem Cells

Abstract

Reactive oxygen species (ROS) can be generated by defective endogenous reduction of oxygen by cellular enzymes or in the mitochondrial respiratory pathway, as well as by exogenous exposure to UV or environmental damaging agents. Regulation of intracellular ROS levels is critical since increases above normal concentrations lead to oxidative stress and DNA damage. A growing body of evidence indicates that the inability to regulate high levels of ROS leading to alteration of cellular homeostasis or defective repair of ROS-induced damage lies at the root of diseases characterized by both neurodegeneration and bone marrow failure as well as cancer. That these diseases may be reflective of the dynamic ability of cells to respond to ROS through developmental stages and aging lies in the similarities between phenotypes at the cellular level. This review summarizes work linking the ability to regulate intracellular ROS to the hematopoietic stem cell phenotype, aging, and disease.

Ssb1 and Ssb2 cooperate to regulate mouse hematopoietic stem and progenitor cells by resolving replicative stress

“…[55][56][57][58] FA is a polygenic human syndrome characterized by aberrant DNA repair and with stem cell defects, leading to BM failure. 56,59,60 In murine models of FA, BM failure can only be induced by physiological activation of HSCs out of a quiescent state (eg, through the induction of type 1 interferon).…”

Accumulation of DNA damage in the aged hematopoietic stem cell compartment

“…Evidence supporting this model includes the strong correlation between increased ROS levels in human CD34+ bone marrow cells and decreased function of these cells in transplant experiments (110). ROS levels also are increased in HSCs from aged mice that diminished long-term reconstitution potential, and genomic rearrangements are more frequent in primitive cells with high levels of ROS (111). Additionally, the ability of HSCs to serially transplant was significantly improved in ATM deficient mice when they were treated with the ROS scavenging antioxidant NAC (112).…”

APE2 Zf-GRF facilitates 3′-5′ resection of DNA damage following oxidative stress

“…This presents a major challenge to genomic stability (3)(4)(5)(6) and is implicated in the pathogenesis of multiple human diseases, including cancer and neurodegenerative disorders (7,8). Abundant DNA damage from oxidative stress constitutes ∼10% of all DNA lesions and includes oxidative DNA damage, such as base damage, sugar moiety damage, apurinic/apyrimidinic (AP) sites, DNA single-strand breaks (SSBs), and double-strand breaks (DSBs) (2,6).…”