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FOXO3 Transcription Factor Is Essential for Protecting Hematopoietic Stem and Progenitor Cells from Oxidative DNA Damage
| Content Provider | Scilit |
|---|---|
| Author | Bigarella, Carolina L. Li, Jianfeng Rimmelé, Pauline Liang, Raymond Sobol, Robert W. Ghaffari, Saghi |
| Copyright Year | 2017 |
| Description | Journal: Journal of Biological Chemistry 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 defective $Foxo3^{−/−}$ 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 that $Foxo3^{−/−}$ 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 in $Foxo3^{−/−}$ primitive hematopoietic cells. Treating mice in vivo with N-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 in $Foxo3^{−/−}$ mutant HSPC is at least partially reversible. Collectively, our findings suggest that FOXO3 serves as a protector of HSC genomic stability and health. |
| Related Links | http://www.jbc.org/content/292/7/3005.full.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5314194/pdf http://www.jbc.org/article/S0021925820407379/pdf |
| Ending Page | 3015 |
| Page Count | 11 |
| Starting Page | 3005 |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| DOI | 10.1074/jbc.m116.769455 |
| Journal | Journal of Biological Chemistry |
| Issue Number | 7 |
| Volume Number | 292 |
| Language | English |
| Publisher | Elsevier BV |
| Publisher Date | 2017-02-01 |
| Access Restriction | Open |
| Subject Keyword | Journal: Journal of Biological Chemistry Cell Tissue Engineering Dna Damage Response Base Excision Repair (ber) Hematopoietic Stem Cells Oxidative Dna Damage Oxidative Stress Reactive Oxygen Species (ros) |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
