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Volume 27
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10.3390/ijms27031278
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

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

by
Eisuke Hishida
1,
Masaki Watanabe
1,
Takeru Sasaki
1,
Tatsuya Ashida
1,
Keisuke Shimada
2,
Tadashi Okamura
3,
Takashi Agui
4 and
Nobuya Sasaki
1,*
1
Laboratory of Laboratory Animal Science and Medicine, School of Veterinary Medicine, Kitasato University, Towada 034-8628, Aomori, Japan
2
Laboratory of Experimental Animal Science, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu 069-8501, Hokkaido, Japan
3
Department of Laboratory Animal Medicine, National Institute of Global Health and Medicine—Japan Institute for Health and Security (JIHS), Shinjuku 162-8655, Tokyo, Japan
4
Laboratory of Laboratory Animal Science and Medicine, Department of Applied Veterinary Sciences, Graduate School of Veterinary Medicine, Sapporo 060-0819, Hokkaido, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2026, 27(3), 1278; https://doi.org/10.3390/ijms27031278
Submission received: 25 December 2025 / Revised: 23 January 2026 / Accepted: 26 January 2026 / Published: 27 January 2026
(This article belongs to the Special Issue Advances in Animal Molecular Genetics)
Versions Notes

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.
Keywords: HMCES; radiosensitivity; DNA double-strand break repair; end-joining repair; xhs1 locus HMCES; radiosensitivity; DNA double-strand break repair; end-joining repair; xhs1 locus

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MDPI and ACS Style

Hishida, E.; Watanabe, M.; Sasaki, T.; Ashida, T.; Shimada, K.; Okamura, T.; Agui, T.; Sasaki, N. Identification of HMCES as the Core Genetic Determinant Underlying the xhs1 Radiosensitivity Locus in LEA/LEC Rats. Int. J. Mol. Sci. 2026, 27, 1278. https://doi.org/10.3390/ijms27031278

AMA Style

Hishida E, Watanabe M, Sasaki T, Ashida T, Shimada K, Okamura T, Agui T, Sasaki N. Identification of HMCES as the Core Genetic Determinant Underlying the xhs1 Radiosensitivity Locus in LEA/LEC Rats. International Journal of Molecular Sciences. 2026; 27(3):1278. https://doi.org/10.3390/ijms27031278

Chicago/Turabian Style

Hishida, Eisuke, Masaki Watanabe, Takeru Sasaki, Tatsuya Ashida, Keisuke Shimada, Tadashi Okamura, Takashi Agui, and Nobuya Sasaki. 2026. "Identification of HMCES as the Core Genetic Determinant Underlying the xhs1 Radiosensitivity Locus in LEA/LEC Rats" International Journal of Molecular Sciences 27, no. 3: 1278. https://doi.org/10.3390/ijms27031278

APA Style

Hishida, E., Watanabe, M., Sasaki, T., Ashida, T., Shimada, K., Okamura, T., Agui, T., & Sasaki, N. (2026). Identification of HMCES as the Core Genetic Determinant Underlying the xhs1 Radiosensitivity Locus in LEA/LEC Rats. International Journal of Molecular Sciences, 27(3), 1278. https://doi.org/10.3390/ijms27031278

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