| Summary: | The ataxia-telangiectasia mutated (<i>atm</i>) gene is activated in response to genotoxic stress and leads to activation of the <i>tp53</i> tumor suppressor gene which induces either senescence or apoptosis as tumor suppressive mechanisms. Atm also serves non-canonical functions in the response to oxidative stress and chromatin reorganization. We previously reported that overexpression of the epigenetic regulator and oncogene Ubiquitin Like with PHD and Ring Finger Domains 1 (UHRF1) in zebrafish hepatocytes resulted in <i>tp53</i>-dependent hepatocyte senescence, a small liver and larval lethality. We investigated the role of <i>atm</i> on UHRF1-mediated phenotypes by generating zebrafish <i>atm</i> mutants. <i>atm</i><sup>−/−</sup> adults were viable but had reduction in fertility. Embryos developed normally but were protected from lethality caused by etoposide or H<sub>2</sub>O<sub>2</sub> exposure and failed to fully upregulate Tp53 targets or oxidative stress response genes in response to these treatments. In contrast to the finding that Tp53 prevents the small liver phenotype caused by UHRF1 overexpression, <i>atm</i> mutation and exposure to H<sub>2</sub>O<sub>2</sub> further reduced the liver size in UHRF1 overexpressing larvae whereas treatment with the antioxidant N-acetyl cysteine suppressed this phenotype. We conclude that UHRF1 overexpression in hepatocytes causes oxidative stress, and that loss of <i>atm</i> further enhances this, triggering elimination of these precancerous cells, leading to a small liver.
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