Gadd45a deletion aggravates hematopoietic stem cell dysfunction in ATM-deficient mice.
10.1007/s13238-013-0017-9
- Author:
Yulin CHEN
1
;
Runan YANG
;
Peng GUO
;
Zhenyu JU
Author Information
1. Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, 311121, China.
- Publication Type:Journal Article
- MeSH:
Animals;
Ataxia Telangiectasia Mutated Proteins;
genetics;
B-Lymphocytes;
pathology;
Cell Cycle Proteins;
genetics;
Cell Proliferation;
Cyclin-Dependent Kinase Inhibitor p21;
metabolism;
DNA Damage;
Hematopoietic Stem Cell Transplantation;
Hematopoietic Stem Cells;
metabolism;
pathology;
Leukemia;
genetics;
pathology;
Lymphoma;
genetics;
pathology;
Mice, Knockout;
Neoplasm Metastasis;
Nuclear Proteins;
genetics;
T-Lymphocytes;
pathology;
Tumor Suppressor Protein p53;
metabolism
- From:
Protein & Cell
2014;5(1):80-89
- CountryChina
- Language:English
-
Abstract:
Ataxia telangiectasia mutated (ATM) kinase plays an essential role in the maintenance of genomic stability. ATM-deficient (ATM(-/-)) mice exhibit hematopoietic stem cell (HSC) dysfunction and a high incidence of lymphoma. Gadd45a controls cell cycle arrest, apoptosis and DNA repair, and is involved in the ATM-p53 mediated DNA damage response. However, the role of Gadd45a in regulating the functionality of ATM(-/-) HSCs is unknown. Here we report that Gadd45a deletion did not rescue the defects of T-cells and B-cells development in ATM(-/-) mice. Instead, ATM and Gadd45a double knockout (ATM(-/-) Gadd45a(-/-)) HSCs exhibited an aggravated defect in long-term self-renewal capacity compared to ATM(-/-) HSCs in HSC transplantation experiments. Further experiments revealed that the aggravated defect of ATM(-/-) Gadd45a(-/-) HSCs was due to a reduction of cell proliferation, associated with an accumulation of DNA damage and subsequent activation of DNA damage response including an up-regulation of p53-p21 signaling pathway. Additionally, ATM(-/-) Gadd45a(-/-) mice showed an increased incidence of hematopoietic malignancies, as well as an increased rate of metastasis than ATM(-/-) mice. In conclusion, Gadd45a deletion aggravated the DNA damage accumulation, which subsequently resulted in a further impaired self-renewal capacity and an increased malignant transformation in ATM(-/-) HSCs.
