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MT000190

UniProt Annotations

Entry Information

Gene Name	DNA replication helicase/nuclease 2
Protein Entry	DNA2_HUMAN
UniProt ID	P51530
Species	Human

Comments

Comment type	Description
Alternative Products	Event=Alternative splicing; Named isoforms=4; Name=1; IsoId=P51530-1; Sequence=Displayed; Name=2; IsoId=P51530-2; Sequence=VSP_021870, VSP_021871; Note=No experimental confirmation available.; Name=3; IsoId=P51530-3; Sequence=VSP_021869; Note=No experimental confirmation available.; Name=4; IsoId=P51530-4; Sequence=VSP_044185; Note=No experimental confirmation available.;
Catalytic Activity	ATP + H(2)O = ADP + phosphate. {ECO:0000269\|PubMed:16595800}.
Cofactor	Name=[4Fe-4S] cluster; Xref=ChEBI:CHEBI:49883; Evidence={ECO:0000250}; Note=Binds 1 [4Fe-4S] cluster. {ECO:0000250};
Disease	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 6 (PEOA6) [MIM:615156]: 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. {ECO:0000269\|PubMed:23352259}. Note=The disease is caused by mutations affecting the gene represented in this entry.
Disease	Seckel syndrome 8 (SCKL8) [MIM:615807]: 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 mental retardation. {ECO:0000269\|PubMed:24389050}. Note=The disease is caused by mutations affecting the gene represented in this entry.
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 weak and its function remains largely unclear. Helicase activity may promote the motion of DNA2 on the flap, helping the nuclease function. {ECO:0000269\|PubMed:16595799, ECO:0000269\|PubMed:16595800, ECO:0000269\|PubMed:18995831, ECO:0000269\|PubMed:19487465, ECO:0000269\|PubMed:21325134, ECO:0000269\|PubMed:21572043, ECO:0000269\|PubMed:22570407, ECO:0000269\|PubMed:22570476}.
Ptm	Acetylated by EP300, leading to stimulate the 5'-3' endonuclease, the 5'-3' helicase and DNA-dependent ATPase activities, possibly by increasing DNA substrate affinity. {ECO:0000269\|PubMed:20019387}.
Sequence Caution	Sequence=AAH28188.1; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305}; Sequence=AAH63664.1; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305}; Sequence=BAA07647.1; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305}; Sequence=CAI17237.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305}; Sequence=CAI17238.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
Similarity	Belongs to the DNA2/NAM7 helicase family. {ECO:0000305}.
Subcellular Location	Nucleus. Mitochondrion. Note=Was initially reported to be exclusively mitochondrial (PubMed:18995831). However, it was later shown to localize both in mitochondrion and nucleus (PubMed:19487465). {ECO:0000269\|PubMed:18995831, ECO:0000269\|PubMed:19487465}.
Subunit	Interacts with BLM and WDHD1. {ECO:0000269\|PubMed:21325134, ECO:0000269\|PubMed:22570476}.