Recombinant Human DNA replication ATP-dependent helicase/nuclease DNA2 (DNA2), partial

Function

Key enzyme involved in DNA replication and DNA repair in nucleus and mitochondrion. Involved in Okazaki fragments processing by cleaving long flaps that escape FEN1: flaps that are longer than 27 nucleotides are coated by replication protein A complex (RPA), leading to recruit DNA2 which cleaves the flap until it is too short to bind RPA and becomes a substrate for FEN1. Also involved in 5'-end resection of DNA during double-strand break (DSB) repair: recruited by BLM and mediates the cleavage of 5'-ssDNA, while the 3'-ssDNA cleavage is prevented by the presence of RPA. Also involved in DNA replication checkpoint independently of Okazaki fragments processing. Possesses different enzymatic activities, such as single-stranded DNA (ssDNA)-dependent ATPase, 5'-3' helicase and endonuclease activities. While the ATPase and endonuclease activities are well-defined and play a key role in Okazaki fragments processing and DSB repair, the 5'-3' DNA helicase activity is subject to debate. According to various reports, the helicase activity is absent to weak and its function remains largely unclear. Helicase activity may promote the motion of DNA2 on the flap, helping the nuclease function

Subcellular Location

Nucleus; Mitochondrion

Disease Association

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 6 (PEOA6) : A disorder characterized by muscle weakness, mainly affecting the lower limbs, external ophthalmoplegia, exercise intolerance, and mitochondrial DNA deletions on muscle biopsy. Symptoms may appear in childhood or adulthood and show slow progression. [The disease is caused by variants affecting the gene represented in this entry] | Seckel syndrome 8 (SCKL8) : A rare autosomal recessive disorder characterized by proportionate dwarfism of prenatal onset associated with low birth weight, growth retardation, severe microcephaly with a bird-headed like appearance, and intellectual disability. [The disease is caused by variants affecting the gene represented in this entry] | Rothmund-Thomson syndrome 4 (RTS4) : A form of Rothmund-Thomson syndrome, a disorder characterized by sparse hair, eyebrows and eyelashes, juvenile cataracts, and poikiloderma, a genodermatosis presenting with mottled pigmentation, telangiectasia and epidermal atrophy. Additional features are short stature, dysplastic nails, and skeletal and dental abnormalities. Inheritance is autosomal recessive. RTS4 patients also exhibit microcephaly and photosensitivity with bullae. Growth failure is severe, with some individuals showing signs of growth hormone or combined pituitary hormone deficiency. [The disease is caused by variants affecting the gene represented in this entry]

Subunit

Interacts with BLM and WDHD1

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• Deloukas P. et al. The DNA sequence and comparative analysis of human chromosome 10. — Nature (2004)
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). — Genome Res. (2004)
• Kim J.H. et al. Isolation of human Dna2 endonuclease and characterization of its enzymatic properties. — Nucleic Acids Res. (2006)
• Masuda-Sasa T. et al. Biochemical analysis of human Dna2. — Nucleic Acids Res. (2006)
• Zheng L. et al. Human DNA2 is a mitochondrial nuclease/helicase for efficient processing of DNA replication and repair intermediates. — Mol. Cell (2008)
• Duxin J.P. et al. Human Dna2 is a nuclear and mitochondrial DNA maintenance protein. — Mol. Cell. Biol. (2009)
• Balakrishnan L. et al. Acetylation of Dna2 endonuclease/helicase and flap endonuclease 1 by p300 promotes DNA stability by creating long flap intermediates. — J. Biol. Chem. (2010)