# Caffeine May Delay the Radiation-Induced Nucleoshuttling of the ATM Kinase and Reduce the Recognition of the DNA Double-Strand Breaks in Human Cells

## TL;DR

Caffeine may delay how cells detect DNA damage from radiation, especially in cells that are already resistant to radiation.

## Contribution

This study shows caffeine can act as an 'X-molecule' to influence ATM nucleoshuttling and DSB recognition in human cells.

## Key findings

- Caffeine inhibits radiation-induced ATM nucleoshuttling and DSB recognition in radioresistant cells.
- AD and NF1 cells already have low DSB recognition, so caffeine has no additional effect on them.
- X-protein mutations and caffeine both reduce ATM activity, but caffeine's effect is more pronounced in radioresistant cells.

## Abstract

Since 2014, a model of the individual response to ionizing radiation (IR), based on the radiation-induced nucleoshuttling of the ATM protein kinase (RIANS), has been developed by our lab: after irradiation, ATM dimers monomerize in cytoplasm and diffuse into the nucleus to trigger both recognition and repair of DNA double-strand breaks (DSB), the key-damage of IR response. Moderate radiosensitivity is generally caused by heterozygous mutations of ATM substrates (called X-proteins) that are over-expressed in cytoplasm and form complexes with ATM monomers, which reduces and/or delays the RIANS and DSB recognition. Here, we asked whether molecules, rather than X-proteins, can also influence RIANS. Caffeine was chosen as a potential “X-molecule” candidate. After incubation of cells with caffeine, cutaneous fibroblasts from an apparently healthy radioresistant donor, a patient suffering from Alzheimer’s disease (AD) and another suffering from neurofibromatosis type 1 (NF1) were exposed to X-rays. The functionality of ATM-dependent DSB repair and signaling was evaluated. We report here that caffeine molecule interaction with ATM leads to the inhibition of DSB recognition. This effect is significant in radioresistant cells. Conversely, in the AD and NF1 cells, the DSB recognition is already so low that caffeine does not provide any additional molecular effect.