Isoform-specific p73 knockout mice reveal a novel role for delta Np73 in the DNA damage response pathway

• Published in: Genes & development Vol. 24; no. 6; pp. 549 - 560
• Main Authors: Wilhelm, Margareta T, Rufini, Alessandro, Wetzel, Monica K, Tsuchihara, Katsuya, Inoue, Satoshi, Tomasini, Richard, Itie-Youten, Annick, Wakeham, Andrew, Arsenian-Henriksson, Marie, Melino, Gerry, Kaplan, David R, Miller, Freda D, Mak, Tak W
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 15.03.2010
• Subjects: Animals; Apoptosis - genetics; Ataxia Telangiectasia Mutated Proteins; Brain - pathology; Cell Cycle Proteins - metabolism; Cell Line; Cell Line, Tumor; Cells, Cultured; DNA Damage; DNA Repair - physiology; DNA-Binding Proteins - metabolism; Female; Fertility - genetics; Gene Expression Regulation; HCT116 Cells; Humans; Longevity - genetics; Male; Medicin och hälsovetenskap; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Neurodegenerative Diseases - genetics; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phosphorylation; Protein Isoforms - genetics; Protein Serine-Threonine Kinases - metabolism; Research Paper; Signal Transduction; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - metabolism
• ISSN: 0890-9369; 1549-5477; 1549-5477
• DOI: 10.1101/gad.1873910

Mice with a complete deficiency of p73 have severe neurological and immunological defects due to the absence of all TAp73 and DeltaNp73 isoforms. As part of our ongoing program to distinguish the biological functions of these isoforms, we generated mice that are selectively deficient for the DeltaNp73 isoform. Mice lacking DeltaNp73 (DeltaNp73(-/-) mice) are viable and fertile but display signs of neurodegeneration. Cells from DeltaNp73(-/-) mice are sensitized to DNA-damaging agents and show an increase in p53-dependent apoptosis. When analyzing the DNA damage response (DDR) in DeltaNp73(-/-) cells, we discovered a completely new role for DeltaNp73 in inhibiting the molecular signal emanating from a DNA break to the DDR pathway. We found that DeltaNp73 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 DeltaNp73 expression show enhanced resistance to chemotherapy.