MCB Accepts, published online ahead of print on 5 February 2007

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Mol. Cell. Biol. doi:10.1128/MCB.01652-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Disruption of the FEN-1/PCNA interaction results in DNA replication defects, pulmonary hypoplasia, pancytopenia, and newborn lethality in mice

Li Zheng, Huifang Dai, Junzhuan Qiu, Qin Huang, and Binghui Shen^*

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

^* To whom correspondence should be addressed. Email: bshen{at}coh.org.

The interaction between flap endonuclease-1 (FEN-1) and proliferation cell nuclear antigen (PCNA) is critical for faithful and efficient Okazaki fragment maturation. In a living cell, this interaction is probably important for PCNA to load FEN-1 to the replication fork, to coordinate the sequential functions of FEN-1 and other enzymes, and to stimulate its enzyme activity. The FEN-1/PCNA interaction is mediated by the motif ³³⁷QGRLDDFFK³⁴⁵ of FEN-1, such that a F343AF344A (FFAA) mutant cannot bind to PCNA, but retains its nuclease activities. To determine the physiological roles of the FEN-1/PCNA interaction in a mammalian system, we knocked the F343AF344A (FFAA) Fen1 mutation into the Fen1 gene locus of mice. FFAA/FFAA mutant MEF cells underwent DNA replication and division at a slower pace, and FFAA/FFAA mutant embryos display significant defects in growth and development, particularly in the lung and blood system. All newborn FFAA mutant pups die at birth, likely due to pulmonary hypoplasia and pancytopenia. Collectively, our data demonstrate the importance of the FEN-1/PCNA complex in DNA replication and the embryonic development in mice.

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