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

Abstract

In addition to promoting cell death and senescence, p53 also has important cellular survival functions. A mutant p53, lacking a proline-rich domain (p53^ΔP), 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 p53^ΔP and p53^−/− cells were equally resistant to many DNA damaging agents, p53^ΔP 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 p53^ΔP 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, p53^ΔP mice show enhanced survival after IR relative to p53^−/− mice. Suppression or deletion of MGMT expression in p53^ΔP 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.