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Molecular and Cellular Biology, July 2008, p. 4310-4319, Vol. 28, No. 13
0270-7306/08/$08.00+0     doi:10.1128/MCB.00200-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Nucleolar Localization and Dynamic Roles of Flap Endonuclease 1 in Ribosomal DNA Replication and Damage Repair{triangledown} ,{dagger}

Zhigang Guo,{ddagger} Limin Qian,{ddagger} Ren Liu, Huifang Dai, Mian Zhou, Li Zheng, and Binghui Shen*

Department of Radiation Biology, City of Hope National Medical Center and Beckman Research Institute, Duarte, California 91010

Received 7 February 2008/ Returned for modification 25 February 2008/ Accepted 15 April 2008

Despite the wealth of information available on the biochemical functions and our recent findings of its roles in genome stability and cancer avoidance of the structure-specific flap endonuclease 1 (FEN1), its cellular compartmentalization and dynamics corresponding to its involvement in various DNA metabolic pathways are not yet elucidated. Several years ago, we demonstrated that FEN1 migrates into the nucleus in response to DNA damage and under certain cell cycle conditions. In the current paper, we found that FEN1 is superaccumulated in the nucleolus and plays a role in the resolution of stalled DNA replication forks formed at the sites of natural replication fork barriers. In response to UV irradiation and upon phosphorylation, FEN1 migrates to nuclear plasma to participate in the resolution of UV cross-links on DNA, most likely employing its concerted action of exonuclease and gap-dependent endonuclease activities. Based on yeast complementation experiments, the mutation of Ser187Asp, mimicking constant phosphorylation, excludes FEN1 from nucleolar accumulation. The replacement of Ser187 by Ala, eliminating the only phosphorylation site, retains FEN1 in nucleoli. Both of the mutations cause UV sensitivity, impair cellular UV damage repair capacity, and decline overall cellular survivorship.

* Corresponding author. Mailing address: Department of Radiation Biology, City of Hope National Medical Center and Beckman Research Institute, 1500 East Duarte Road, Duarte, CA 91010. Phone: (626) 301-8879. Fax: (626) 301-8280. E-mail: bshen{at}coh.org

{triangledown} Published ahead of print on 28 April 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Z.G. and L.Q. contributed to the work equally.

Molecular and Cellular Biology, July 2008, p. 4310-4319, Vol. 28, No. 13
0270-7306/08/$08.00+0     doi:10.1128/MCB.00200-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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