title: FOXO3 Transcription Factor Is Essential for Protecting Hematopoietic Stem and Progenitor Cells from Oxidative DNA Damage.
abstract: Accumulation 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 defectiveFoxo3-/-HSC cycling, among many other deficiencies. Here, we show that loss of FOXO3 leads to the accumulation of DNA damage in primitive hematopoietic stem and progenitor cells (HSPC), associated specifically with reduced expression of genes implicated in the repair of oxidative DNA damage. We provide further evidence thatFoxo3-/-HSPC are defective in DNA damage repair. Specifically, we show that the base excision repair pathway, the main pathway utilized for the repair of oxidative DNA damage, is compromised inFoxo3-/-primitive hematopoietic cells. Treating micein vivowithN-acetylcysteine reduces ROS levels, rescues HSC cycling defects, and partially mitigates HSPC DNA damage. These results indicate that DNA damage accrued as a result of elevated ROS inFoxo3-/-mutant HSPC is at least partially reversible. Collectively, our findings suggest that FOXO3 serves as a protector of HSC genomic stability and health.
authors.affiliation: From the Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Carolina L
authors.initials: CL
authors.lastname: Bigarella
authors.affiliation: the Department of Oncologic Sciences, University of South Alabama Mitchell Cancer Institute, Mobile, Alabama 36604.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Li
authors.affiliation: From the Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Pauline
authors.initials: P
authors.lastname: Rimmelé
authors.affiliation: From the Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029.|the Developmental and Stem Cell Biology Multidisciplinary Training Area.
authors.forename: Raymond
authors.initials: R
authors.lastname: Liang
authors.affiliation: the Department of Oncologic Sciences, University of South Alabama Mitchell Cancer Institute, Mobile, Alabama 36604.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sobol
authors.affiliation: From the Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, saghi.ghaffari@mssm.edu.|the Developmental and Stem Cell Biology Multidisciplinary Training Area.|Department of Medicine, Division of Hematology and, Oncology.|Black Family Stem Cell Institute, and.|Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Saghi
authors.initials: S
authors.lastname: Ghaffari
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D004249:DNA Damage; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; D017382:Reactive Oxygen Species; D000111:Acetylcysteine
keywords: DNA damage response; FOXO; FOXO3; ROS; aging; base excision repair (BER); hematopoietic stem cells; oxidative DNA damage; oxidative stress; reactive oxygen species (ROS)