Gadd45a regulates hematopoietic stem cell stress responses in mice

Blood. 2014 Feb 6;123(6):851-62. doi: 10.1182/blood-2013-05-504084. Epub 2013 Dec 26.


Gadd45a has been involved in DNA damage response and in many malignancies, including leukemia. However, the function of Gadd45a in hematopoietic stem cells (HSCs) remains unknown. Here, we reported that Gadd45a-deficient (Gadd45a(-/-)) mice showed a normal hematologic phenotype under homeostatic conditions. However, following 5-fluorouracil treatment, Gadd45a(-/-) HSCs exhibited a faster recovery, associated with an increase in the proliferation rate. Interestingly, young Gadd45a(-/-) HSCs showed enhanced reconstitution ability in serial transplantation. Following ionizing radiation (IR), young Gadd45a(-/-) HSCs exhibited an increased resistance to IR-induced DNA damage, associated with a decrease in the apoptosis rate and delayed DNA repair. The significantly higher level of DNA damage in Gadd45a(-/-) HSCs ultimately promoted B-cell leukemia in further transplanted recipient mice. In old mice, Gadd45a(-/-) HSCs were functionally equal to wild-type HSCs but exhibited more DNA damage accumulation and increased sensitivity to IR than wild-type HSCs. In conclusion, Gadd45a plays a significant role in HSC stress responses. Gadd45a deficiency leads to DNA damage accumulation and impairment in apoptosis after exposure to IR, which increases the susceptibility of leukemogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / radiation effects
  • Blotting, Western
  • Cell Cycle / drug effects
  • Cell Cycle / radiation effects
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Cycle Proteins / physiology*
  • Cell Proliferation / drug effects
  • Cell Proliferation / radiation effects
  • Cells, Cultured
  • DNA Damage / drug effects*
  • DNA Damage / radiation effects
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Fluorouracil / pharmacology
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / pathology*
  • Hematopoietic Stem Cells / radiation effects
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Nuclear Proteins / physiology*
  • RNA, Messenger / genetics
  • Radiation, Ionizing*
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stress, Physiological / drug effects*
  • Stress, Physiological / radiation effects


  • Antimetabolites, Antineoplastic
  • Cell Cycle Proteins
  • GADD45A protein, human
  • Gadd45a protein, mouse
  • Nuclear Proteins
  • RNA, Messenger
  • Fluorouracil