title: Human DNA2 is a mitochondrial nuclease/helicase for efficient processing of DNA replication and repair intermediates.
abstract: DNA2, a helicase/nuclease family member, plays versatile roles in processing DNA intermediates during DNA replication and repair. Yeast Dna2 (yDna2) is essential in RNA primer removal during nuclear DNA replication and is important in repairing UV damage, base damage, and double-strand breaks. Our data demonstrate that, surprisingly, human DNA2 (hDNA2) does not localize to nuclei, as it lacks a nuclear localization signal equivalent to that present in yDna2. Instead, hDNA2 migrates to the mitochondria, interacts with mitochondrial DNA polymerase gamma, and significantly stimulates polymerase activity. We further demonstrate that hDNA2 and flap endonuclease 1 synergistically process intermediate 5' flap structures occurring in DNA replication and long-patch base excision repair (LP-BER) in mitochondria. Depletion of hDNA2 from a mitochondrial extract reduces its efficiency in RNA primer removal and LP-BER. Taken together, our studies illustrate an evolutionarily diversified role of hDNA2 in mitochondrial DNA replication and repair in a mammalian system.
authors.affiliation: Department of Radiation Biology, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA 91010, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zheng
authors.forename: Mian
authors.initials: M
authors.lastname: Zhou
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Guo
authors.forename: Huiming
authors.initials: H
authors.lastname: Lu
authors.forename: Limin
authors.initials: L
authors.lastname: Qian
authors.forename: Huifang
authors.initials: H
authors.lastname: Dai
authors.forename: Junzhuan
authors.initials: J
authors.lastname: Qiu
authors.forename: Elena
authors.initials: E
authors.lastname: Yakubovskaya
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Bogenhagen
authors.forename: Bruce
authors.initials: B
authors.lastname: Demple
authors.forename: Binghui
authors.initials: B
authors.lastname: Shen
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D002384:Catalysis; D002467:Cell Nucleus / Q000201:enzymology; D003593:Cytoplasm / Q000201:enzymology; D004265:DNA Helicases / Q000378:metabolism*; D004260:DNA Repair; D004261:DNA Replication; D003851:Deoxyribonucleases / Q000378:metabolism; D045585:Flap Endonucleases / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000201:enzymology; D014176:Protein Biosynthesis
chemical_list: D006360:Heat-Shock Proteins; D003851:Deoxyribonucleases; D045585:Flap Endonucleases; D000251:Adenosine Triphosphatases; D004265:DNA Helicases; C509908:DNA2 protein, human