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 P), 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 P and p53 â '/â ' cells were equally resistant to many DNA damaging agents, p53 P 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 P 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 P mice show enhanced survival after IR relative to p53 â '/â ' mice. Suppression or deletion of MGMT expression in p53 P 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.