期刊
NUCLEIC ACIDS RESEARCH
卷 46, 期 21, 页码 11315-11325出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gky911
关键词
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资金
- National Basic Research Program of China [2015CB910600]
- National Key R&D Program of China [2017YFA0503900]
- Zhejiang Provincial Natural Science Foundation for Outstanding Young Scientists [LR16C050002]
- National Natural Science Foundation of China [31210103904, 31500656, 31670819]
- National Institutes of Health [R01CA073764, R50CA211397]
Human flap endonuclease 1 (hFEN1) is a structure-specific nuclease essential for DNA replication and repair processes. hFEN1 has 5 ' flap removal activity, as well as gap endonuclease activity that is critical for restarting stalled replication forks. Here, we report the crystal structures of wild-type and mutant hFEN1 proteins in complex with DNA substrates, followed by mutagenesis studies that provide mechanistic insight into the protein-protein interactions of hFEN1. We found that in an alpha-helix forming the helical gateway of hFEN1 recognizes the 5 ' flap prior to its threading into the active site for cleavage. We also found that the beta-pin region is rigidified into a short helix in R192F hFEN1-DNA structures, suppressing its gap endonuclease activity and cycle-dependent kinase interactions. Our findings suggest that a single mutation at the primary methylation site can alter the function of hFEN1 and provide insight into the role of the beta-pin region in hFEN1 protein interactions that are essential for DNA replication and repair.
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