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. 2024 Nov;29(11):951-965.
doi: 10.1111/gtc.13156. Epub 2024 Sep 8.

Dose-dependent effects of histone methyltransferase NSD2 on site-specific double-strand break repair

Koh Iwasaki  1 , Akari Tojo  1 , Haruka Kobayashi  1 , Kai Shimizu  1 , Yoshitaka Kamimura  2 , Yasunori Horikoshi  2 , Atsuhiko Fukuto  2   3 , Jiying Sun  2 , Manabu Yasui  4 , Masamitsu Honma  4 , Atsushi Okabe  5 , Ryoji Fujiki  5   6 , Nakako Izumi Nakajima  7 , Atsushi Kaneda  5 , Satoshi Tashiro  2 , Akira Sassa  1 , Kiyoe Ura  1
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Free article

Dose-dependent effects of histone methyltransferase NSD2 on site-specific double-strand break repair

Koh Iwasaki et al. Genes Cells. 2024 Nov.
Free article

Abstract

Histone modifications are catalyzed and recognized by specific proteins to regulate dynamic DNA metabolism processes. NSD2 is a histone H3 lysine 36 (H3K36)-specific methyltransferase that is associated with both various transcription regulators and DNA repair factors. Specifically, it has been implicated in the repair of DNA double-strand breaks (DSBs); however, the role of NSD2 during DSB repair remains enigmatic. Here, we show that NSD2 does not accumulate at DSB sites and that it is not further mobilized by DSB formation. Using three different DSB repair reporter systems, which contained the endonuclease site in the active thymidine kinase gene (TK) locus, we demonstrated separate dose-dependent effects of NSD2 on homologous recombination (HR), canonical-non-homologous end joining (c-NHEJ), and non-canonical-NHEJ (non-c-NHEJ). Endogenous NSD2 has a role in repressing non-c-NHEJ, without affecting DSB repair efficiency by HR or total NHEJ. Furthermore, overexpression of NSD2 promotes c-NHEJ repair and suppresses HR repair. Therefore, we propose that NSD2 has functions in chromatin integrity at the active regions during DSB repair.

Keywords: DNA double‐strand break repair; H3K36me; NSD2; histone methylation; homologous recombination; nonhomologous end joining.

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References

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