# Natural Genetic Variation Impacts Stress-Induced Quiescence and Regeneration in Response to Rapamycin

## TL;DR

This study shows that natural genetic differences affect how rapamycin influences cell recovery after radiation, with mitochondrial function playing a key role.

## Contribution

The study identifies mitochondrial dynamics as a key factor in genetic variation affecting rapamycin response.

## Key findings

- Genetic background significantly influences rapamycin's effect on quiescence and regeneration after radiation.
- Mitochondrial dynamics are more strongly linked to rapamycin sensitivity than DNA damage repair processes.
- Natural genetic variation in DGRP reveals critical differences in therapeutic response to rapamycin.

## Abstract

In response to ionizing radiation (IR), both adult and cancer stem cells enter reversible cell cycle arrest at the G1/S transition to evade apoptosis and subsequently re-enter the cell cycle to regenerate damaged tissue. Entry into and exit from this arrest, known as “quiescence,” is governed by the inhibition of mTORC1. The pharmacological suppression of mTORC1 with rapamycin prevents quiescent stem cells from re-entering the cell cycle and impairs tissue regeneration. Rapamycin holds great therapeutic promise in preventing tumor regrowth from dormant cancer stem cells. Yet the extent to which genetic background impacts the known variation in the pharmacological response of rapamycin remains unknown. Here, we show that natural genetic variation across the Drosophila Genetics Reference Panel (DGRP) drives substantial differences in the rapamycin-mediated suppression of post-IR quiescence and regeneration. To define the basis of this differential sensitivity, we examined mitochondrial turnover and DNA damage repair—processes controlling IR-induced dormancy. Our analyses reveal that variation in rapamycin sensitivity is more strongly associated with differences in mitochondrial dynamics than with DNA damage response following radiation. Together, these findings demonstrate that genetic background is a critical determinant of rapamycin efficacy and identify mitochondrial regulation as a key mechanism underlying differential therapeutic response.