Activation of DNA damage response pathways in human mesenchymal stem cells exposed to cisplatin or γ-irradiation

Cell Cycle. 2011 Nov 1;10(21):3768-77. doi: 10.4161/cc.10.21.17972. Epub 2011 Nov 1.


DNA damaging agents are widely used in treatment of hematogical malignancies and solid tumors. While effects on hematopoietic stem cells have been characterized, less is known about the DNA damage response in human mesenchymal stem cells (hMSCs) in the bone marrow stroma, progenitors of osteoblasts, chondrocytes and adipocytes. To elucidate the response of undifferentiated hMSCs to γ-irradiation and cisplatin, key DNA damage responses have been characterised in hMSCs from normal adult donors. Cisplatin and γ-irradiation activated the DNA damage response in hMSCs, including induction of p53 and p21, and activation of PI3 kinase-related protein kinase (PIKK)-dependent phosphorylation of histone H2AX on serine 139, and replication protein A2 on serine4/serine8. Chemical inhibition of ATM or DNA-PK reduced DNA damage-induced phosphorylation of H2AX, indicating a role for both PIKKs in the response of hMSCs to DNA damage. Consistent with repair of DNA strand breaks, γ-H2AX staining decreased by 24 hours following gamma-irradiation. γ-Irradiation arrested hMSCs in the G 1 phase of the cell cycle, while cisplatin induced S-phase arrest, mediated in part by the ATR/Chk1 checkpoint pathway. In hMSCs isolated from a chronic lymphocytic leukemia (CLL) patient, p53 and p21 were induced by cisplatin and γ-irradiation, while RPA2 was phosphorylated on serine4/8 in particular following cisplatin. Compared to peripheral blood lymphocytes or the leukemia cell line K562, both normal hMSCs and CLL-derived hMSCs were more resistant to cisplatin and γ-irradiation. These results provide insights into key pathways mediating the response of bone marrow-derived hMSCs to DNA damaging agents used in cancer treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Checkpoints / radiation effects
  • Cisplatin / pharmacology*
  • Cyclin-Dependent Kinase Inhibitor p21 / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • DNA Adducts
  • DNA Breaks / radiation effects
  • DNA Damage*
  • DNA Repair / drug effects
  • DNA Repair / radiation effects
  • Gamma Rays*
  • Histones / metabolism
  • Humans
  • Mesenchymal Stem Cells / drug effects*
  • Mesenchymal Stem Cells / radiation effects
  • Mutagens / pharmacology*
  • Phosphorylation
  • Tumor Suppressor Protein p53 / drug effects
  • Tumor Suppressor Protein p53 / metabolism


  • Cyclin-Dependent Kinase Inhibitor p21
  • DNA Adducts
  • H2AX protein, human
  • Histones
  • Mutagens
  • Tumor Suppressor Protein p53
  • Cisplatin