Hyperactivation of ATM Upon DNA-PKcs Inhibition Modulates P53 Dynamics and Cell Fate in Response to DNA Damage

Overview

Journal Mol Biol Cell

Specialties Cell Biology
Molecular Biology

Date 2016 Jun 10

PMID 27280387

Citations 33

Authors

Ana Finzel

Andrea Grybowski

Jette Strasen

Elena Cristiano

Alexander Loewer

Affiliations

Soon will be listed here.

Abstract

A functional DNA damage response is essential for maintaining genome integrity in the presence of DNA double-strand breaks. It is mainly coordinated by the kinases ATM, ATR, and DNA-PKcs, which control the repair of broken DNA strands and relay the damage signal to the tumor suppressor p53 to induce cell cycle arrest, apoptosis, or senescence. Although many functions of the individual kinases have been identified, it remains unclear how they act in concert to ensure faithful processing of the damage signal. Using specific inhibitors and quantitative analysis at the single-cell level, we systematically characterize the contribution of each kinase for regulating p53 activity. Our results reveal a new regulatory interplay in which loss of DNA-PKcs function leads to hyperactivation of ATM and amplification of the p53 response, sensitizing cells for damage-induced senescence. This interplay determines the outcome of treatment regimens combining irradiation with DNA-PKcs inhibitors in a p53-dependent manner.

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