FOXO3 Transcription Factor Is Essential for Protecting Hematopoietic Stem and Progenitor Cells from Oxidative DNA Damage

Abstract

Edited by Xiao-Fan WangAccumulation of damaged DNA in hematopoietic stem cells (HSC) is associated with chromosomal abnormalities, genomic instability, and HSC aging and might promote hematological malignancies with age. Despite this, the regulatory pathways implicated in the HSC DNA damage response have not been fully elucidated. One of the sources of DNA damage is reactive oxygen species (ROS) generated by both exogenous and endogenous insults. Balancing ROS levels in HSC requires FOXO3, which is an essential transcription factor for HSC maintenance implicated in HSC aging. Elevated ROS levels result in defective

Metformin induces FOXO3-dependent fetal hemoglobin production in human primary erythroid cells

“…Our analysis found that individuals with nonsynonymous variants in FOXO3 had lower HbF levels. FOXO3 is a transcription factor that has been shown to be essential for erythroid maturation in mouse models, 22,24 and it is an important regulator of glucose metabolism, 17,60,61 among other functions 14,[62][63][64][65][66] ; however, it has not previously been implicated in HbF regulation. Here, we presented functional studies supporting the hypothesis that FOXO3 is a partial positive regulator of HbF, likely along with other factors; knockdown of FOXO3 in HSPCs from normal individuals reduced g-globin expression and production without altering b-globin expression and production.…”

The Roles of FoxO Transcription Factors in Regulation of Bone Cells Function

“…FoxOs maintain quiescence and self-renewal of HSCs mainly through transcriptional regulation of cell cycle arrest and oxidative stress resistance (Figure 4a). The loss of FoxO3 in HSCs not only leads to oxidative DNA damage in HSCs by interfering in the base excision repair pathway [46], but also damages the HSC pool with regulating the cell cycle through ROS-independent modulations of the tumor suppressor protein ataxia telangiectasia mutated (ATM) and p16INK4a and ROS-mediated activation of p19ARF/p53/p21CIP1/WAF1/Sdi1 tumor suppressor pathways [47]. Likewise, conditional deletion of FoxO1, FoxO3, and FoxO4 in the adult mice hematopoietic system decreases the expression of antioxidant enzyme genes, including catalase, glutathione peroxidase 1 (Gpx-1), and superoxide dismutase Sod1, Sod2, and Sod3, resulting in ROS over-accumulation.…”

IFN-1 Bid crosstalk: foe or friend to stem cells

“…Intracellular reactive oxygen species (ROS) are a byproduct of mitochondrial oxidative phosphorylation that are generated by the respiratory chain primarily in the form of superoxide anions (O 2 − ) and are immediately transformed by mitochondrial superoxide dismutase (MnSOD) to hydrogen peroxide (H 2 O 2 ) (5). HSPCs are highly sensitive to ROS and under normal physiological condition; ROS levels are tightly regulated to prevent hematopoietic cell damage (6)(7)(8). Accumulating evidence indicates that the inability to regulate high levels of ROS can lead to impaired stem and progenitor cell homeostasis and bone marrow failure (6)(7)(8)(9).…”

“…HSPCs are highly sensitive to ROS and under normal physiological condition; ROS levels are tightly regulated to prevent hematopoietic cell damage (6)(7)(8). Accumulating evidence indicates that the inability to regulate high levels of ROS can lead to impaired stem and progenitor cell homeostasis and bone marrow failure (6)(7)(8)(9). Evidence also suggest a role for chronic oxidative stress in the progression of radiation-induced acute and late hematopoietic syndromes (10,11), stem cell aging and (12) degenerative diseases (13), whereas ROS scavengers improve HSPC function and engraftment (9,14).…”