Gadd45a deletion aggravates hematopoietic stem cell dysfunction in ATM-deficient mice.
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.
Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, 311121, China.
Yulin
Y
Chen
Runan
R
Yang
Peng
P
Guo
Zhenyu
Z
Ju
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics*; D001402:B-Lymphocytes / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics*; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D007938:Leukemia / Q000235:genetics / Q000473:pathology; D008223:Lymphoma / Q000235:genetics / Q000473:pathology; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000235:genetics*; D013601:T-Lymphocytes / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000097642:GADD45 Proteins
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins