The proline rich domain of p53 is dispensable for MGMT-dependent DNA repair and cell survival following alkylation damage

Cell Death Differ. 2017 Nov;24(11):1925-1936. doi: 10.1038/cdd.2017.116. Epub 2017 Jul 28.

Abstract

In addition to promoting cell death and senescence, p53 also has important cellular survival functions. A mutant p53, lacking a proline-rich domain (p53ΔP), that is deficient in controlling both cell death and cell cycle arrest, was employed to determine the biological means by which p53 mediates survival upon DNA damage. While p53ΔP and p53-/- cells were equally resistant to many DNA damaging agents, p53ΔP cells showed an exquisite resistance to high doses of the alkylating agent Diazald (N-Methyl-N-(p-tolylsulfonyl)nitrosamide), as compared to cells completely deficient for p53 function. We determined that p53ΔP was capable of transcribing the repair gene, MGMT (O6-methylguanine-DNA methyltransferase) after irradiation or alkylation damage, resulting in DNA repair and cell survival. Consistent with these observations, p53ΔP mice show enhanced survival after IR relative to p53-/- mice. Suppression or deletion of MGMT expression in p53ΔP cells inhibited DNA repair and survival after alkylation damage, whereas MGMT overexpression in p53-deficient cells facilitated DNA repair and conferred survival advantage. This study shows that when cell death and cell cycle arrest pathways are inhibited, p53 can still mediate MGMT-dependent repair, to promote cell survival upon DNA damage.

MeSH terms

  • Alkylation
  • Animals
  • Apoptosis / radiation effects
  • Apoptosis Regulatory Proteins / metabolism
  • Cell Cycle Checkpoints / radiation effects
  • Cell Line, Tumor
  • Cell Survival / radiation effects
  • Cellular Senescence
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • DNA Damage*
  • DNA Repair* / radiation effects
  • Gene Silencing / radiation effects
  • Mice
  • O(6)-Methylguanine-DNA Methyltransferase / genetics
  • O(6)-Methylguanine-DNA Methyltransferase / metabolism*
  • Proline / metabolism
  • Protein Domains
  • Proto-Oncogene Proteins / metabolism
  • Radiation, Ionizing
  • Structure-Activity Relationship
  • Tumor Suppressor Protein p53 / chemistry*
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Apoptosis Regulatory Proteins
  • BBC3 protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Proto-Oncogene Proteins
  • Tumor Suppressor Protein p53
  • Proline
  • O(6)-Methylguanine-DNA Methyltransferase