Wuho Is a New Member in Maintaining Genome Stability through its Interaction with Flap Endonuclease 1

I. Cheng Cheng, Betty Chamay Chen, Hung Hsun Shuai, Fan Ching Chien, Peilin Chen, Tao Shih Hsieh

研究成果: 雜誌貢獻期刊論文同行評審

14 引文 斯高帕斯(Scopus)

摘要

Replication forks are vulnerable to wayward nuclease activities. We report here our discovery of a new member in guarding genome stability at replication forks. We previously isolated a Drosophila mutation, wuho (wh, no progeny), characterized by a severe fertility defect and affecting expression of a protein (WH) in a family of conserved proteins with multiple WD40 repeats. Knockdown of WH by siRNA in Drosophila, mouse, and human cultured cells results in DNA damage with strand breaks and apoptosis through ATM/Chk2/p53 signaling pathway. Mice with mWh knockout are early embryonic lethal and display DNA damage. We identify that the flap endonuclease 1 (FEN1) is one of the interacting proteins. Fluorescence microscopy showed the localization of WH at the site of nascent DNA synthesis along with other replication proteins, including FEN1 and PCNA. We show that WH is able to modulate FEN1’s endonucleolytic activities depending on the substrate DNA structure. The stimulatory or inhibitory effects of WH on FEN1’s flap versus gap endonuclease activities are consistent with the proposed WH’s functions in protecting the integrity of replication fork. These results suggest that wh is a new member of the guardians of genome stability because it regulates FEN1’s potential DNA cleavage threat near the site of replication.

原文???core.languages.en_GB???
文章編號e1002349
期刊PLoS Biology
14
發行號1
DOIs
出版狀態已出版 - 11 1月 2016

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