TDP2は、前立腺上皮細胞においてアンドロゲンによるゲノム不安定性を抑制する

付記する学位プログラム名: 充実した健康長寿社会を築く総合医療開発リーダー育成プログラム京都大学新制・課程博士博士(医学)甲第23090号医博第4717号新制||医||1050(附属図書館)京都大学大学院医学研究科医学専攻(主査)教授 篠原 隆司, 教授 小川 修, 教授 溝脇 尚志学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

ATM suppresses c-Myc overexpression in the mammary epithelium in response to estrogen

ATM遺伝子変異による乳癌発症機構を解明 --HBOC症候群の乳腺特異的発癌機構の解明に貢献--. 京都大学プレスリリース. 2023-02-09.ATM gene mutation carriers are predisposed to estrogen-receptor-positive breast cancer (BC). ATM prevents BC oncogenesis by activating p53 in every cell; however, much remains unknown about tissue-specific oncogenesis after ATM loss. Here, we report that ATM controls the early transcriptional response to estrogens. This response depends on topoisomerase II (TOP2), which generates TOP2-DNA double-strand break (DSB) complexes and rejoins the breaks. When TOP2-mediated ligation fails, ATM facilitates DSB repair. After estrogen exposure, TOP2-dependent DSBs arise at the c-MYC enhancer in human BC cells, and their defective repair changes the activation profile of enhancers and induces the overexpression of many genes, including the c-MYC oncogene. CRISPR/Cas9 cleavage at the enhancer also causes c-MYC overexpression, indicating that this DSB causes c-MYC overexpression. Estrogen treatment induced c-Myc protein overexpression in mammary epithelial cells of ATM-deficient mice. In conclusion, ATM suppresses the c-Myc-driven proliferative effects of estrogens, possibly explaining such tissue-specific oncogenesis

A Comprehensive Exploration of Outlier Detection in Unstructured Data for Enhanced Business Intelligence Using Machine Learning

Due to the rapid growth of online data, it is evident that social informatics faces a significant obstacle. The task of effectively utilizing this abundance of information for business intelligence purposes and extracting valuable insights from it across diverse and heterogeneous platforms presents a daunting challenge. Coordinating AI with business knowledge stands apart as an essential worry in the ongoing scene. Customarily, exceptions were many times excused as boisterous information, bringing about the deficiency of relevant data. This paper highlights the need to rethink how outliers are handled and shed light on the primary research challenges in this mining subfield. It presents a thorough scientific categorization of different Business Knowledge strategies and diagrams their ongoing application areas. Also, the paper talks about future exploration bearings and proposals to overcome any barrier concerning oddities in information examination, consequently empowering more successful business methodologies. This work plans to improve the usage of tremendous web-based information hotspots for better business insight results

TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands

Androgens stimulate the proliferation of epithelial cells in the prostate by activating topoisomerase 2 (TOP2) and regulating the transcription of target genes. TOP2 resolves the entanglement of genomic DNA by transiently generating double‐strand breaks (DSBs), where TOP2 homodimers covalently bind to 5′ DSB ends, called TOP2‐DNA cleavage complexes (TOP2ccs). When TOP2 fails to rejoin TOP2ccs generating stalled TOP2ccs, tyrosyl DNA phosphodiesterase‐2 (TDP2) removes 5′ TOP2 adducts from stalled TOP2ccs prior to the ligation of the DSBs by nonhomologous end joining (NHEJ), the dominant DSB repair pathway in G0/G1 phases. We previously showed that estrogens frequently generate stalled TOP2ccs in G0/G1 phases. Here, we show that physiological concentrations of androgens induce several DSBs in individual human prostate cancer cells during G1 phase, and loss of TDP2 causes a five times higher number of androgen‐induced chromosome breaks in mitotic chromosome spreads. Intraperitoneally injected androgens induce several DSBs in individual epithelial cells of the prostate in TDP2‐deficient mice, even at 20 hr postinjection. In conclusion, physiological concentrations of androgens have very strong genotoxicity, most likely by generating stalled TOP2ccs.This work was conducted through the Joint Research Program of the Radiation Biology Center, Kyoto University and supported by the following grants: a Grant‐in‐Aid from the Ministry of Education, Science, Sport and Culture to S.T. (KAKENHI 25650006, 23221005 and 16H06306) and H.S. (KAKENHI 16H02953, 18H04900 and 19H04267), the Takeda Research Foundation, and Mitsubishi Foundation (to H.S.) and JSPS Core‐to‐Core Program, A. Advanced Research Networks (to S.T.), and Andalusian Government grants SAF2010‐21017, SAF2013‐47343‐P, SAF2014‐55532‐R, CVI‐7948 and FEDER funds (to F.C.‐L.).Peer reviewe