研究チームが癌の突然変異を促進する重要な酵素の役割を発見(UC Irvine-led research team discovers role of key enzymes that drive cancer mutations)

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2024-03-18 カリフォルニア大学校アーバイン校(UCI)

カリフォルニア大学アーバイン校の研究チームが、APOBEC3AとAPOBEC3B酵素が腫瘍ゲノムのDNAを修飾し、がん変異を促進する重要な役割を発見しました。これにより、がん変異を抑制する新しい介入戦略の可能性が提供されます。研究では、APOBEC3AとAPOBEC3Bが特定のDNA構造を検出し、腫瘍ゲノム内の異なる位置で変異を引き起こすプロセスが特定されました。これに基づき、各酵素に直接ターゲットを絞った新しい治療法の開発が期待されます。この研究は、Nature Communications誌にオンラインで発表されました。

<関連情報>

APOBEC3AとAPOBEC3Bの脱アミナーゼ活性がメソスケールDNAの特徴に影響し、腫瘍の突然変異のランドスケープが形成される Mesoscale DNA features impact APOBEC3A and APOBEC3B deaminase activity and shape tumor mutational landscapes

Ambrocio Sanchez,Pedro Ortega,Ramin Sakhtemani,Lavanya Manjunath,Sunwoo Oh,Elodie Bournique,Alexandrea Becker,Kyumin Kim,Cameron Durfee,Nuri Alpay Temiz,Xiaojiang S. Chen,Reuben S. Harris,Michael S. Lawrence & Rémi Buisson
Nature Communications  Published:18 March 2024
DOI:https://doi.org/10.1038/s41467-024-45909-5

研究チームが癌の突然変異を促進する重要な酵素の役割を発見(UC Irvine-led research team discovers role of key enzymes that drive cancer mutations)

Abstract

Antiviral DNA cytosine deaminases APOBEC3A and APOBEC3B are major sources of mutations in cancer by catalyzing cytosine-to-uracil deamination. APOBEC3A preferentially targets single-stranded DNAs, with a noted affinity for DNA regions that adopt stem-loop secondary structures. However, the detailed substrate preferences of APOBEC3A and APOBEC3B have not been fully established, and the specific influence of the DNA sequence on APOBEC3A and APOBEC3B deaminase activity remains to be investigated. Here, we find that APOBEC3B also selectively targets DNA stem-loop structures, and they are distinct from those subjected to deamination by APOBEC3A. We develop Oligo-seq, an in vitro sequencing-based method to identify specific sequence contexts promoting APOBEC3A and APOBEC3B activity. Through this approach, we demonstrate that APOBEC3A and APOBEC3B deaminase activity is strongly regulated by specific sequences surrounding the targeted cytosine. Moreover, we identify the structural features of APOBEC3B and APOBEC3A responsible for their substrate preferences. Importantly, we determine that APOBEC3B-induced mutations in hairpin-forming sequences within tumor genomes differ from the DNA stem-loop sequences mutated by APOBEC3A. Together, our study provides evidence that APOBEC3A and APOBEC3B can generate distinct mutation landscapes in cancer genomes, driven by their unique substrate selectivity.

細胞遺伝子工学
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