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

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.
Authors	I-Cheng Cheng, Betty Chamay Chen, Hung-Hsun Shuai, Fan-Ching Chien, Peilin Chen, Tao-shih Hsieh
Journal	PLoS biology (PLoS Biol) Vol. 14 Issue 1 Pg. e1002349 (Jan 2016) ISSN: 1545-7885 [Electronic] United States
PMID	26751069 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Carrier Proteins Drosophila Proteins Proliferating Cell Nuclear Antigen Tumor Suppressor Protein p53 WDR4 protein, human wuho protein, Drosophila Fen1 protein, mouse Flap Endonucleases FEN1 protein, human GTP-Binding Proteins WDR4 protein, mouse
Topics	Animals Apoptosis Carrier Proteins DNA Replication Drosophila Proteins Drosophila melanogaster Flap Endonucleases (metabolism) GTP-Binding Proteins (metabolism) Genomic Instability HCT116 Cells Humans Mice Mice, Knockout Proliferating Cell Nuclear Antigen (metabolism) Tumor Suppressor Protein p53 (metabolism)

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