Gadd45a deletion aggravates hematopoietic stem cell dysfunction in ATM-deficient mice

Protein Cell. 2014 Jan;5(1):80-9. doi: 10.1007/s13238-013-0017-9. Epub 2014 Jan 29.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Hematopoietic Stem Cells / pathology*
  • Leukemia / genetics
  • Leukemia / pathology
  • Lymphoma / genetics
  • Lymphoma / pathology
  • Mice, Knockout
  • Neoplasm Metastasis
  • Nuclear Proteins / genetics*
  • T-Lymphocytes / pathology
  • Tumor Suppressor Protein p53 / metabolism


  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Gadd45a protein, mouse
  • Nuclear Proteins
  • Tumor Suppressor Protein p53
  • Ataxia Telangiectasia Mutated Proteins