# Tolerance thresholds underlie responses to DNA damage during germline development

## TL;DR

This study shows that germ cells have built-in DNA damage tolerance thresholds that protect genomic integrity during development.

## Contribution

The study identifies DNA damage tolerance thresholds as a novel protective mechanism in germline development.

## Key findings

- Mitotic germ cells are sensitive to DNA double-strand breaks in a dose-dependent manner.
- Postmitotic germ cells show higher tolerance to DNA damage and complete oogenesis despite genome damage.
- DSBs caused by transposable elements trigger germ cell loss independently of gene disruption.

## Abstract

In this study, Jansen et al. use a Drosophila dysgenesis model to demonstrate that tolerance thresholds to DNA damage constitute a crucial protective mechanism for maintaining germline genomic integrity and germ cell survival. They show that DNA double-strand breaks (DSBs) induced by P-element transposition cause mitotic germ cell loss through the activation of a CHK2 checkpoint and in a DSB dose-dependent manner, while postmitotic germ cells have higher DSB tolerance and progress further through oogenesis.

Selfish DNA modules like transposable elements (TEs) are particularly active in the germline, the lineage that passes genetic information across generations. New TE insertions can disrupt genes and impair the functionality and viability of germ cells. However, we found that in P–M hybrid dysgenesis in Drosophila, a sterility syndrome triggered by the P-element DNA transposon, germ cells harbor unexpectedly few new TE insertions despite accumulating DNA double-strand breaks (DSBs) and inducing cell cycle arrest. Using an engineered CRISPR–Cas9 system, we show that generating DSBs at silenced P-elements or other noncoding sequences is sufficient to induce germ cell loss independently of gene disruption. Indeed, we demonstrate that both developing and adult mitotic germ cells are sensitive to DSBs in a dosage-dependent manner. Following the mitotic-to-meiotic transition, however, germ cells become more tolerant to DSBs, completing oogenesis regardless of the accumulated genome damage. Our findings establish DNA damage tolerance thresholds as crucial safeguards of genome integrity during germline development.