P51530 · DNA2_HUMAN
- ProteinDNA replication ATP-dependent helicase/nuclease DNA2
- GeneDNA2
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids1060 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
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.
Catalytic activity
- ATP + H2O = ADP + H+ + phosphate
Cofactor
Note: Binds 1 [4Fe-4S] cluster.
Features
Showing features for binding site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 136 | [4Fe-4S] cluster (UniProtKB | ChEBI) | ||||
Sequence: C | ||||||
Binding site | 393 | [4Fe-4S] cluster (UniProtKB | ChEBI) | ||||
Sequence: C | ||||||
Binding site | 396 | [4Fe-4S] cluster (UniProtKB | ChEBI) | ||||
Sequence: C | ||||||
Binding site | 402 | [4Fe-4S] cluster (UniProtKB | ChEBI) | ||||
Sequence: C | ||||||
Binding site | 648-655 | ATP (UniProtKB | ChEBI) | ||||
Sequence: GMPGTGKT |
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameDNA replication ATP-dependent helicase/nuclease DNA2
- Short nameshDNA2
- Alternative names
Including 2 domains:
- Recommended nameDNA replication nuclease DNA2
- EC number
- Recommended nameDNA replication ATP-dependent helicase DNA2
- EC number
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionP51530
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Keywords
- Cellular component
Disease & Variants
Involvement in disease
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 6 (PEOA6)
- Note
- DescriptionA 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.
- See alsoMIM:615156
Natural variants in PEOA6
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_069905 | 198 | R>H | in PEOA6; the mutant protein has a complete loss of nuclease activity and severely impaired helicase activity; consistent with a loss of function mutation; dbSNP:rs1272393477 | |
VAR_089692 | 221 | A>G | in PEOA6; uncertain significance; modestly decreased of both ATP hydrolysis activity and nuclease activity | |
VAR_069906 | 227 | K>E | in PEOA6; the mutant protein has significantly reduced nuclease and helicase activity; consistent with a loss of function mutation; dbSNP:rs760412883 | |
VAR_089693 | 552 | S>L | in PEOA6; uncertain significance; decreased both ATP hydrolysis activity and nuclease activity | |
VAR_069907 | 637 | V>I | in PEOA6; the mutant protein has decreased nuclease activity (30% of wild-type) and enhanced helicase activity; consistent with a loss of function mutation; dbSNP:rs746522359 | |
VAR_089694 | 640 | S>L | in PEOA6; likely pathogenic; abolished both ATP hydrolysis activity and nuclease activity | |
VAR_089696 | 956 | R>H | in PEOA6; uncertain significance; no effect on both ATP hydrolysis activity and nuclease activity |
Seckel syndrome 8 (SCKL8)
- Note
- DescriptionA 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.
- See alsoMIM:615807
Natural variants in SCKL8
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_089695 | 655 | T>A | in SCKL8; likely pathogenic |
Rothmund-Thomson syndrome 4 (RTS4)
- Note
- DescriptionA 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.
- See alsoMIM:620819
Natural variants in RTS4
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_089691 | 48 | L>P | in RTS4; likely pathogenic |
Features
Showing features for natural variant, mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | VAR_089691 | 48 | in RTS4; likely pathogenic | |||
Sequence: L → P | ||||||
Natural variant | VAR_069905 | 198 | in PEOA6; the mutant protein has a complete loss of nuclease activity and severely impaired helicase activity; consistent with a loss of function mutation; dbSNP:rs1272393477 | |||
Sequence: R → H | ||||||
Natural variant | VAR_089692 | 221 | in PEOA6; uncertain significance; modestly decreased of both ATP hydrolysis activity and nuclease activity | |||
Sequence: A → G | ||||||
Natural variant | VAR_069906 | 227 | in PEOA6; the mutant protein has significantly reduced nuclease and helicase activity; consistent with a loss of function mutation; dbSNP:rs760412883 | |||
Sequence: K → E | ||||||
Mutagenesis | 277 | Abolishes ability to resect DNA in present of BLM. | ||||
Sequence: D → A | ||||||
Natural variant | VAR_089693 | 552 | in PEOA6; uncertain significance; decreased both ATP hydrolysis activity and nuclease activity | |||
Sequence: S → L | ||||||
Natural variant | VAR_069907 | 637 | in PEOA6; the mutant protein has decreased nuclease activity (30% of wild-type) and enhanced helicase activity; consistent with a loss of function mutation; dbSNP:rs746522359 | |||
Sequence: V → I | ||||||
Natural variant | VAR_089694 | 640 | in PEOA6; likely pathogenic; abolished both ATP hydrolysis activity and nuclease activity | |||
Sequence: S → L | ||||||
Mutagenesis | 654 | Abolishes ability to unwind DNA, while it does not affect ability to resect DNA. | ||||
Sequence: K → E | ||||||
Natural variant | VAR_089695 | 655 | in SCKL8; likely pathogenic | |||
Sequence: T → A | ||||||
Natural variant | VAR_089696 | 956 | in PEOA6; uncertain significance; no effect on both ATP hydrolysis activity and nuclease activity | |||
Sequence: R → H |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 1,072 variants from UniProt as well as other sources including ClinVar and dbSNP.
Keywords
- Disease
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for chain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000080712 | 1-1060 | DNA replication ATP-dependent helicase/nuclease DNA2 | |||
Sequence: MEQLNELELLMEKSFWEEAELPAELFQKKVVASFPRTVLSTGMDNRYLVLAVNTVQNKEGNCEKRLVITASQSLENKELCILRNDWCSVPVEPGDIIHLEGDCTSDTWIIDKDFGYLILYPDMLISGTSIASSIRCMRRAVLSETFRSSDPATRQMLIGTVLHEVFQKAINNSFAPEKLQELAFQTIQEIRHLKEMYRLNLSQDEIKQEVEDYLPSFCKWAGDFMHKNTSTDFPQMQLSLPSDNSKDNSTCNIEVVKPMDIEESIWSPRFGLKGKIDVTVGVKIHRGYKTKYKIMPLELKTGKESNSIEHRSQVVLYTLLSQERRADPEAGLLLYLKTGQMYPVPANHLDKRELLKLRNQMAFSLFHRISKSATRQKTQLASLPQIIEEEKTCKYCSQIGNCALYSRAVEQQMDCSSVPIVMLPKIEEETQHLKQTHLEYFSLWCLMLTLESQSKDNKKNHQNIWLMPASEMEKSGSCIGNLIRMEHVKIVCDGQYLHNFQCKHGAIPVTNLMAGDRVIVSGEERSLFALSRGYVKEINMTTVTCLLDRNLSVLPESTLFRLDQEEKNCDIDTPLGNLSKLMENTFVSKKLRDLIIDFREPQFISYLSSVLPHDAKDTVACILKGLNKPQRQAMKKVLLSKDYTLIVGMPGTGKTTTICTLVRILYACGFSVLLTSYTHSAVDNILLKLAKFKIGFLRLGQIQKVHPAIQQFTEQEICRSKSIKSLALLEELYNSQLIVATTCMGINHPIFSRKIFDFCIVDEASQISQPICLGPLFFSRRFVLVGDHQQLPPLVLNREARALGMSESLFKRLEQNKSAVVQLTVQYRMNSKIMSLSNKLTYEGKLECGSDKVANAVINLRHFKDVKLELEFYADYSDNPWLMGVFEPNNPVCFLNTDKVPAPEQVEKGGVSNVTEAKLIVFLTSIFVKAGCSPSDIGIIAPYRQQLKIINDLLARSIGMVEVNTVDKYQGRDKSIVLVSFVRSNKDGTVGELLKDWRRLNVAITRAKHKLILLGCVPSLNCYPPLEKLLNHLNSEKLIIDLPSREHESLCHILGDFQRE |
Post-translational modification
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.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Structure
Family & Domains
Features
Showing features for region.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 81-519 | Nuclease activity | ||||
Sequence: ILRNDWCSVPVEPGDIIHLEGDCTSDTWIIDKDFGYLILYPDMLISGTSIASSIRCMRRAVLSETFRSSDPATRQMLIGTVLHEVFQKAINNSFAPEKLQELAFQTIQEIRHLKEMYRLNLSQDEIKQEVEDYLPSFCKWAGDFMHKNTSTDFPQMQLSLPSDNSKDNSTCNIEVVKPMDIEESIWSPRFGLKGKIDVTVGVKIHRGYKTKYKIMPLELKTGKESNSIEHRSQVVLYTLLSQERRADPEAGLLLYLKTGQMYPVPANHLDKRELLKLRNQMAFSLFHRISKSATRQKTQLASLPQIIEEEKTCKYCSQIGNCALYSRAVEQQMDCSSVPIVMLPKIEEETQHLKQTHLEYFSLWCLMLTLESQSKDNKKNHQNIWLMPASEMEKSGSCIGNLIRMEHVKIVCDGQYLHNFQCKHGAIPVTNLMAGDRVI | ||||||
Region | 520-1060 | Helicase activity | ||||
Sequence: VSGEERSLFALSRGYVKEINMTTVTCLLDRNLSVLPESTLFRLDQEEKNCDIDTPLGNLSKLMENTFVSKKLRDLIIDFREPQFISYLSSVLPHDAKDTVACILKGLNKPQRQAMKKVLLSKDYTLIVGMPGTGKTTTICTLVRILYACGFSVLLTSYTHSAVDNILLKLAKFKIGFLRLGQIQKVHPAIQQFTEQEICRSKSIKSLALLEELYNSQLIVATTCMGINHPIFSRKIFDFCIVDEASQISQPICLGPLFFSRRFVLVGDHQQLPPLVLNREARALGMSESLFKRLEQNKSAVVQLTVQYRMNSKIMSLSNKLTYEGKLECGSDKVANAVINLRHFKDVKLELEFYADYSDNPWLMGVFEPNNPVCFLNTDKVPAPEQVEKGGVSNVTEAKLIVFLTSIFVKAGCSPSDIGIIAPYRQQLKIINDLLARSIGMVEVNTVDKYQGRDKSIVLVSFVRSNKDGTVGELLKDWRRLNVAITRAKHKLILLGCVPSLNCYPPLEKLLNHLNSEKLIIDLPSREHESLCHILGDFQRE |
Sequence similarities
Belongs to the DNA2/NAM7 helicase family.
Phylogenomic databases
Family and domain databases
Sequence & Isoforms
- Sequence statusComplete
This entry describes 4 isoforms produced by Alternative splicing.
P51530-1
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- Name1
- Length1,060
- Mass (Da)120,415
- Last updated2006-12-12 v3
- Checksum727D4B268FD75C5A
P51530-2
- Name2
P51530-3
- Name3
- Differences from canonical
- 663-900: Missing
P51530-4
- Name4
- Differences from canonical
- 1040-1060: IDLPSREHESLCHILGDFQRE → SFFFCIWSHLIAL
Computationally mapped potential isoform sequences
There are 3 potential isoforms mapped to this entry
Sequence caution
Features
Showing features for alternative sequence, sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_021869 | 663-900 | in isoform 3 | |||
Sequence: Missing | ||||||
Alternative sequence | VSP_021870 | 664-687 | in isoform 2 | |||
Sequence: ILYACGFSVLLTSYTHSAVDNILL → FRRFIQLSSNLQSKKFADQSPLNP | ||||||
Alternative sequence | VSP_021871 | 688-1060 | in isoform 2 | |||
Sequence: Missing | ||||||
Sequence conflict | 986 | in Ref. 3; AAH28188 | ||||
Sequence: K → N | ||||||
Alternative sequence | VSP_044185 | 1040-1060 | in isoform 4 | |||
Sequence: IDLPSREHESLCHILGDFQRE → SFFFCIWSHLIAL |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
D42046 EMBL· GenBank· DDBJ | BAA07647.1 EMBL· GenBank· DDBJ | mRNA | Different initiation | |
AL136233 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
BC041115 EMBL· GenBank· DDBJ | AAH41115.1 EMBL· GenBank· DDBJ | mRNA | ||
BC053574 EMBL· GenBank· DDBJ | AAH53574.1 EMBL· GenBank· DDBJ | mRNA | ||
BC063664 EMBL· GenBank· DDBJ | AAH63664.1 EMBL· GenBank· DDBJ | mRNA | Different initiation | |
BC111740 EMBL· GenBank· DDBJ | AAI11741.1 EMBL· GenBank· DDBJ | mRNA | ||
BC028188 EMBL· GenBank· DDBJ | AAH28188.1 EMBL· GenBank· DDBJ | mRNA | Different initiation |