DNA polymerase β suppresses somatic indels at CpG dinucleotides in developing cortical neurons

Sugo, Noriyuki; Uchimura, Arikuni; Matsumoto, Risa; Nakayama, Hiro; Fujimoto, Shota; Mizuno, Saya; Higuchi, Mayumi; Toshishige, Masaaki; Satoh, Yasunari; Wakayama, Sayaka; Wakayama, Teruhiko; Yagi, Takeshi

doi:https://doi.org/10.1073/pnas.2506846122

DNA polymerase β suppresses somatic indels at CpG dinucleotides in developing cortical neurons

Sugo, Noriyuki; Uchimura, Arikuni; Matsumoto, Risa et al.

Proceedings of the National Academy of Sciences of the United States of America, 2025, 122(33), e2506846122

アクセス数:12件（2025-11-18 22:26 集計）

固定URL: https://hdl.handle.net/11094/102935

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タイトル	DNA polymerase β suppresses somatic indels at CpG dinucleotides in developing cortical neurons
著者	NRID 1000020372625 1000020372625 researchmap permalink norisugo norisugo Scopus Author ID 6602838748 6602838748 著者名 Sugo, Noriyuki
	NRID 1000020513063 1000020513063 ORCID 0000-0003-2435-7082 0000-0003-2435-7082 researchmap permalink uchimura_a uchimura_a Scopus Author ID 25961229800 25961229800 著者名 Uchimura, Arikuni
	著者名 Matsumoto, Risa
	著者名 Nakayama, Hiro
	著者名 Fujimoto, Shota
	著者名 Mizuno, Saya
	NRID 1000030837795 1000030837795 researchmap permalink mhiguchiy mhiguchiy Scopus Author ID 56768857800 56768857800 著者名 Higuchi, Mayumi
	著者名 Toshishige, Masaaki
	NRID 1000030393424 1000030393424 著者名 Satoh, Yasunari
	NRID 1000010525918 1000010525918 著者名 Wakayama, Sayaka
	NRID 1000040360672 1000040360672 著者名 Wakayama, Teruhiko
	NRID 1000010241241 1000010241241 researchmap permalink takeshiyagi takeshiyagi Scopus Author ID 7402040902 7402040902 著者名 Yagi, Takeshi
キーワード等	CpG demethylation
	DNA repair
	mutagenesis
	neurogenesis
内容	Sugo N., Uchimura A., Matsumoto R., et al. DNA polymerase β suppresses somatic indels at CpG dinucleotides in developing cortical neurons. Proceedings of the National Academy of Sciences of the United States of America 122(33), e2506846122 (2025); https://doi.org/10.1073/pnas.2506846122.
抄録	Somatic mutations in cortical neurons have been implicated in psychiatric disorders. While endogenous DNA damage and repair errors are potential contributors to these mutations during development, the underlying mutagenic mechanism remains unclear. Here, we investigated somatic mutations in immature cortical neurons using mouse somatic cell nuclear transfer-derived embryonic stem cells and whole-genome sequencing. Insertions and deletions (indels) were commonly observed in both repeat and nonrepeat sequences in wild-type cells. The loss of DNA polymerase β (Polβ), an enzyme involved in gap-filling during base excision repair and Ten-Eleven Translocation (TET)-mediated active DNA demethylation, in neural progenitor cells increased indel frequency by ~ninefold at cytosine-phosphate-guanine (CpG) dinucleotides and raised the frequency of structural variants by ~fivefold. These mutations were enriched in neuronal genes, leading to frameshift mutations, amino acid insertions/deletions, and the gain and loss of CpG sites in regulatory regions. Our findings suggest that Polβ preferentially repairs DNA lesions generated at CpG sites by TET-mediated active demethylation, thereby suppressing the mutagenesis that accompanies neuronal gene activation during cortical development.
出版者	National Academy of Sciences
収録物名	Proceedings of the National Academy of Sciences of the United States of America
巻(号)	122(33)
ページ	e2506846122
刊行年月	2025-08-13
言語	英語
ハンドルURL	https://hdl.handle.net/11094/102935
PISSN	00278424
eISSN	10916490
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1073/pnas.2506846122
アクセス権	open access
権利情報	This article is licensed under a Creative Commons Attribution 4.0 International License.
出版タイプ	Version of Record
カテゴリ	学術雑誌論文 Journal Article

資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
DCMI資源タイプ	text
DCTERMS.bibliographicCitation	Proceedings of the National Academy of Sciences of the United States of America. 2025, 122(33), p. e2506846122
DC.title	DNA polymerase β suppresses somatic indels at CpG dinucleotides in developing cortical neurons
DC.creator	Sugo, Noriyuki
	Uchimura, Arikuni
	Matsumoto, Risa
	Nakayama, Hiro
	Fujimoto, Shota
	Mizuno, Saya
	Higuchi, Mayumi
	Toshishige, Masaaki
	Satoh, Yasunari
	Wakayama, Sayaka
	Wakayama, Teruhiko
	Yagi, Takeshi
DC.publisher	National Academy of Sciences
DC.language' scheme='DCTERMS.RFC1766	英語
DC.type' scheme='DCTERMS.DCMIType	text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-08-13
DC.identifier	https://doi.org/10.1073/pnas.2506846122
DC.subject	CpG demethylation
	DNA repair
	mutagenesis
	neurogenesis
DC.description	Sugo N., Uchimura A., Matsumoto R., et al. DNA polymerase β suppresses somatic indels at CpG dinucleotides in developing cortical neurons. Proceedings of the National Academy of Sciences of the United States of America 122(33), e2506846122 (2025); https://doi.org/10.1073/pnas.2506846122.
DCTERMS.abstract	Somatic mutations in cortical neurons have been implicated in psychiatric disorders. While endogenous DNA damage and repair errors are potential contributors to these mutations during development, the underlying mutagenic mechanism remains unclear. Here, we investigated somatic mutations in immature cortical neurons using mouse somatic cell nuclear transfer-derived embryonic stem cells and whole-genome sequencing. Insertions and deletions (indels) were commonly observed in both repeat and nonrepeat sequences in wild-type cells. The loss of DNA polymerase β (Polβ), an enzyme involved in gap-filling during base excision repair and Ten-Eleven Translocation (TET)-mediated active DNA demethylation, in neural progenitor cells increased indel frequency by ~ninefold at cytosine-phosphate-guanine (CpG) dinucleotides and raised the frequency of structural variants by ~fivefold. These mutations were enriched in neuronal genes, leading to frameshift mutations, amino acid insertions/deletions, and the gain and loss of CpG sites in regulatory regions. Our findings suggest that Polβ preferentially repairs DNA lesions generated at CpG sites by TET-mediated active demethylation, thereby suppressing the mutagenesis that accompanies neuronal gene activation during cortical development.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	102935
citation_title	DNA polymerase β suppresses somatic indels at CpG dinucleotides in developing cortical neurons
citation_author	Sugo, Noriyuki
	Uchimura, Arikuni
	Matsumoto, Risa
	Nakayama, Hiro
	Fujimoto, Shota
	Mizuno, Saya
	Higuchi, Mayumi
	Toshishige, Masaaki
	Satoh, Yasunari
	Wakayama, Sayaka
	Wakayama, Teruhiko
	Yagi, Takeshi
citation_publisher	National Academy of Sciences
citation_language	英語
citation_date	2025-08-13
citation_journal_title	Proceedings of the National Academy of Sciences of the United States of America
citation_volume	122
citation_issue	33
citation_firstpage	e2506846122
citation_doi	https://doi.org/10.1073/pnas.2506846122
citation_public_url	https://hdl.handle.net/11094/102935

DNA polymerase β suppresses somatic indels at CpG dinucleotides in developing cortical neurons

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