• 作者：Wenpeng Liu^a ; ^b ; ^d ; Mian Zhou^b ; ¹ ; Zhengke Li^b ; ¹ ; Hongzhi Li^c ; Piotr Polaczek^d ; Huifang Dai^b ; Qiong Wu^b ; Changwei Liu^a ; ^b ; Kenneth K. Karanja^d ; Vencat Popuri^e ; Shu-ou Shan^d ; Katharina Schlacher^e ; Li Zheng^b ; ^{lzheng@coh.org" class="auth_mail" title="E-mail the corresponding author} ; Judith L. Campbell^d ; ^{jcampbel@caltech.edu" class="auth_mail" title="E-mail the corresponding author} ; Binghui Shen^b ; ^{bshen@coh.org" class="auth_mail" title="E-mail the corresponding author}
• 关键词：BLM ; Bloom Syndrome ; CPT ; camptothecin ; DNA2 ; DNA2 nuclease/helicase ; DSB ; double-strand break ; EMSA ; electrophoretic mobility shift assay ; EXO1 ; exonuclesae 1 ; FA ; Fanconi anemia ; FEN1 ; flap endonuclease 1 ; HDR ; homology direct repair ; HTS ; high throughput screening ; MES ; mouse embryonic stem ; MSFC ; Multiple Stage Full Coverage ; NCI DTP ; National Cancer Institute Developmental Therapeutics Program ; RMSD ; root mean square deviation ; RT ; radiotherapy ; SSA ; single-strand annealing ; SSB ; single-str
• 刊名：EBioMedicine
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：6
• 期：Complete
• 页码：73-86
• 全文大小：2142 K

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C5 binds to the helicase domain of DNA2 and inhibits its nuclease, ATPase, and helicase activities.

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C5 inhibits DNA end resection for DNA double strand break repair and restart of stalled replication forks.

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C5 suppresses over-resection of nascent DNA in cells defective in fork protection.

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C5 sensitizes cancer cells to chemotherapeutic agents.

Most chemotherapeutics introduce DNA lesions that block DNA replication to kill cancer cells. Upregulation of DNA repair proteins in cancer cells is a major reason for human cancer to become resistant to chemotherapeutics. DNA repair proteins such as DNA2 nuclease/helicase have long been proposed as targets for sensitization of cancer cells to chemotherapy. We identify a selective DNA2 inhibitor (C5) and demonstrate that DNA2 inhibition by C5 suppresses cancer cells to rescue stalled replication forks. Consequently, it sensitizes cancer cells to replication fork stalling agents such as camptothecin. Thus, C5 is a promising lead compound for developing new anticancer drugs.