Disruption of the DNA damage pathway at different levels results in distinct phenotypes in a murine liver injury model

ABSTRACT: Background and aims: A coordinated stress and regenerative response is important following hepatocyte damage. Here, we investigate the phenotypes that result from genetic abrogation of individual components of the CHK2/ p53/ p21 pathway in a murine model of metabolic liver injury. Methods: NTBC was reduced or withdrawn in Fah / mice lacking Chk2, p53 or p21, and survival, tumor development, liver injury and regeneration were analyzed. Partial hepatectomies were performed and mice were challenged with the Fas-antibody Jo2. Results: In a model of metabolic liver injury, loss of p53, but not of Chk2, impairs the oxidative stress re-sponse and aggravates liver damage, indicative of a direct p53-dependent protective effect on hepatocytes. Cell cycle control during chronic liver injury critically depends on the presence of both p53 and its downstream effector p21. In p53-deficient hepatocytes, unchecked proliferation occurs despite a strong induction of p21, revealing a complex interdependency between p21 and p53. The increased regenerative potential in the absence of p53 cannot fully compensate the surplus injury and is not sufficient to promote survival. Despite the different phenotypes as-sociated with the loss of individual components of the DNA damage response, gene expression patterns are dominated by the severity of liver injury, but reflect distinct effects of p53 on prolif-eration and the anti-oxidative stress response. Conclusion: Characteristic phenotypes result from the genetic abrogation of individual components of the DNA damage response cascade in a liver injury model. The extent to which loss of gene function can be compensated, or affects injury and proliferation, depends on the level at which the cas-cade is interrupted.

ORGANISM(S): Mus musculus

PROVIDER: GSE156852 | GEO | 2020/12/31

REPOSITORIES: GEO