# Identification of HMCES as the Core Genetic Determinant Underlying the xhs1 Radiosensitivity Locus in LEA/LEC Rats

## TL;DR

This study identifies HMCES as the key gene responsible for increased radiosensitivity in LEC rats, linking it to defective DNA repair.

## Contribution

The study establishes HMCES as the causal gene underlying the xhs1 radiosensitivity locus in LEC rats.

## Key findings

- Reduced HMCES protein levels in LEC rats correlate with radiosensitivity.
- HMCES deficiency delays DNA double-strand break repair and increases radiosensitivity.
- Restoring HMCES partially rescues radiosensitivity in LEC-derived cells.

## Abstract

Genomic instability caused by defective DNA double-strand break (DSB) repair is a key determinant of cellular radiosensitivity. The Long–Evans cinnamon (LEC) rat is a rare naturally occurring model with marked radiosensitivity, and a major quantitative trait locus, X-ray hypersensitivity 1 (xhs1), has been mapped to rat chromosome 4; however, the causal mechanism has remained unclear. Here, we investigated the cellular and molecular basis of xhs1-associated radiosensitivity using LEA and LEC rat-derived cells and human cultured cells. Exploratory RNA-seq of pre-hepatitic liver tissue identified a sequence variant within the Hmces transcript in LEC rats. Consistently, HMCES protein levels were markedly reduced in multiple tissues and liver-derived cell lines from LEC rats. Functional analyses showed that reduced HMCES activity prolonged γH2AX signaling after X-ray irradiation, indicating delayed DSB resolution. Clonogenic survival assays demonstrated increased radiosensitivity in HMCES-deficient cells, which was partially rescued by restoring HMCES expression in stable LEA/LEC lines. Moreover, pimEJ5GFP reporter assays revealed significantly decreased end-joining repair activity in HMCES-knockout human cells. Together, these results establish HMCES as a critical mediator of DSB repair and cellular radioresistance, identify HMCES dysfunction as a core genetic determinant underlying xhs1-associated radiosensitivity, and provide mechanistic insight into radiation response architecture in a naturally occurring radiosensitive model.