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

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

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.

Original languageEnglish
Article numbere1002349
JournalPLoS Biology
Volume14
Issue number1
DOIs
StatePublished - 11 Jan 2016

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