Isoform-specific P73 Knockout Mice Reveal a Novel Role for Delta Np73 in the DNA Damage Response Pathway

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2010 Mar 3

PMID 20194434

Citations 133

Authors

Margareta T Wilhelm

Alessandro Rufini

Monica K Wetzel

Katsuya Tsuchihara

Satoshi Inoue

Richard Tomasini

Annick Itie-Youten

Andrew Wakeham

Marie Arsenian-Henriksson

Gerry Melino

David R Kaplan

Freda D Miller

Tak W Mak

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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Mouse cortical organoids reveal key functions of p73 isoforms: TAp73 governs the establishment of the archetypical ventricular-like zones while DNp73 is central in the regulation of neural cell fate.

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