細胞がDNAブリッジを除去する仕組みを解明(“Cutting to Survive”: How Cells Remove DNA Bridges at the Last Moment)

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2025-05-20 韓国基礎科学研究院(IBS)

細胞がDNAブリッジを除去する仕組みを解明(“Cutting to Survive”: How Cells Remove DNA Bridges at the Last Moment)
Figure 1. Functional analysis of the LEM-3 protein and the roles of its domains using the C. elegans model.

細胞分裂時に染色体間にDNAブリッジが残ると、遺伝的不安定性やがんの原因となる。韓国・UNISTとIBSの研究チームは、LEM-3というヌクレアーゼが、分裂の最終段階でこれらのDNAブリッジを切断して除去する「最後の砦」として機能することを解明した。LEM-3は細胞分裂の最終段階に存在するミッドボディに局在し、他の修復経路が機能しない際にDNAブリッジを除去するが、核内に誤って局在すると有害となり、DNAを異常に切断して胚致死を引き起こす。この研究は線虫をモデルに行われ、人間のANKLE1との進化的保存性が確認された。ANKLE1は乳がんや大腸がんに関与することから、本研究はがん予防・治療法の開発に貢献する可能性がある。

<関連情報>

線虫LEM-3/ANKLE1ヌクレアーゼの機能解析から、DNAブリッジ処理にはLEM様ドメインとGIY-YIGドメインが必要であることが明らかになった Functional dissection of the conserved C. elegans LEM-3/ANKLE1 nuclease reveals a crucial requirement for the LEM-like and GIY-YIG domains for DNA bridge processing

Junfang Song , Peter Geary , Khadisha Salemova , John Rouse , Ye Hong , Stéphane G M Rolland , Anton Gartner
Nucleic Acids Research  Published:07 April 2025
DOI:https://doi.org/10.1093/nar/gkaf265

Abstract

Faithful chromosome segregation requires the removal of all DNA bridges physically linking chromatids before the completion of cell division. While several redundant safeguard mechanisms to process these DNA bridges exist from S-phase to late anaphase, the conserved LEM-3/ANKLE1 nuclease has been proposed to be part of a ‘last chance’ mechanism that acts at the midbody to eliminate DNA bridges that persist until late cytokinesis. We show that LEM-3 can cleave a wide range of branched DNA substrates, including flaps, forks, nicked, and intact Holliday junctions. AlphaFold modelling data suggest that the catalytic mechanism of LEM-3/ANKLE1 is conserved, mirroring the mechanism observed in bacterial GIY-YIG nucleases. We present evidence that LEM-3 may form a homodimeric complex on the Holliday junction DNA. LEM-3 LEM-like and GIY-YIG nuclease domains are essential for LEM-3 recruitment to the midbody and its nuclease activity, while its LEM-like domain is sufficient for DNA binding. Finally, we show that preventing LEM-3 nuclear access is important to avoid toxicity, likely caused by branched DNAs cleavage during normal DNA metabolism. Our data suggest that Caenorhabditis elegans LEM-3 acts as a ‘last chance catch-all’ enzyme that processes DNA bridges caused by various perturbations of DNA metabolism just before cells divide.

細胞遺伝子工学
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