Isoform-specific p73 knockout mice reveal a novel role for ΔNp73 in the DNA damage response pathway

Mice with a complete deficiency of p73 have severe neurological and immunological defects due to the absence of all TAp73 and Delta Np73 isoforms. As part of our ongoing program to distinguish the biological functions of these isoforms, we generated mice that are selectively deficient for the Delta Np73 isoform. Mice lacking Delta Np73 (Delta Np73(-/-) mice) are viable and fertile but display signs of neurodegeneration. Cells from Delta Np73(-/-) mice are sensitized to DNA-damaging agents and show an increase in p53-dependent apoptosis. When analyzing the DNA damage response (DDR) in Delta Np73(-/-) cells, we discovered a completely new role for Delta Np73 in inhibiting the molecular signal emanating from a DNA break to the DDR pathway. We found that Delta Np73 localizes directly to the site of DNA damage, can interact with the DNA damage sensor protein 53BP1, and inhibits ATM activation and subsequent p53 phosphorylation. This novel finding may explain why human tumors with high levels of Delta Np73 expression show enhanced resistance to chemotherapy.