DNA2

Summary

DNA2 (DNA replication helicase/nuclease 2, HGNC:2939) is a protein-coding gene on chromosome 10q21.3, encoding DNA replication ATP-dependent helicase/nuclease DNA2 (P51530). Key enzyme involved in DNA replication and DNA repair in nucleus and mitochondrion. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

This gene encodes a member of the DNA2/NAM7 helicase family. The encoded protein is a conserved helicase/nuclease involved in the maintenance of mitochondrial and nuclear DNA stability. Mutations in this gene are associated with autosomal dominant progressive external ophthalmoplegia-6 (PEOA6) and Seckel syndrome 8. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 1763 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial DNA deletion syndrome with progressive myopathy (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 1,044 total — 6 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 102
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_001080449

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2939
Approved symbol	DNA2
Name	DNA replication helicase/nuclease 2
Location	10q21.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0083
Ensembl gene	ENSG00000138346
Ensembl biotype	protein_coding
OMIM	601810
Entrez	1763

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 16 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000358410, ENST00000399179, ENST00000440722, ENST00000478029, ENST00000550357, ENST00000550545, ENST00000551118, ENST00000936790, ENST00000936791, ENST00000936792, ENST00000936793, ENST00000936794, ENST00000936795, ENST00000936796, ENST00000936797, ENST00000936798, ENST00000936799, ENST00000936800, ENST00000936801, ENST00000941878

RefSeq mRNA: 1 — MANE Select: NM_001080449 NM_001080449

CCDS: CCDS44415

Canonical transcript exons

ENST00000358410 — 21 exons

Exon	Start	End
ENSE00000933654	68471791	68471973
ENSE00001536883	68430436	68430660
ENSE00001596452	68444921	68445083
ENSE00001627236	68450028	68450247
ENSE00001641645	68437011	68437241
ENSE00001647298	68442917	68443111
ENSE00001681606	68465667	68465812
ENSE00001712965	68432206	68432315
ENSE00001729648	68468123	68468306
ENSE00001729977	68432394	68432510
ENSE00001771913	68459104	68459235
ENSE00001772574	68431862	68431971
ENSE00001794102	68446296	68446413
ENSE00002334009	68414064	68415107
ENSE00003613396	68469981	68470163
ENSE00003714122	68419803	68419892
ENSE00003719341	68422697	68422890
ENSE00003729621	68416709	68416855
ENSE00003734572	68419034	68419213
ENSE00003742172	68422225	68422429
ENSE00003744106	68422515	68422604

Expression profiles

Bgee: expression breadth ubiquitous, 192 present calls, max score 90.79.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.1828 / max 341.5905, expressed in 1181 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
109759	9.1828	1181

Top tissues by expression

275 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	90.79	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.62	gold quality
Brodmann (1909) area 10	UBERON:0013541	86.83	gold quality
oocyte	CL:0000023	86.37	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.69	gold quality
ventricular zone	UBERON:0003053	84.97	gold quality
ganglionic eminence	UBERON:0004023	82.83	gold quality
embryo	UBERON:0000922	81.07	gold quality
endometrium epithelium	UBERON:0004811	78.74	gold quality
frontal pole	UBERON:0002795	78.66	gold quality
paraflocculus	UBERON:0005351	78.62	gold quality
middle frontal gyrus	UBERON:0002702	77.95	gold quality
cortical plate	UBERON:0005343	76.30	gold quality
right lobe of liver	UBERON:0001114	76.05	gold quality
choroid plexus epithelium	UBERON:0003911	75.58	gold quality
adrenal tissue	UBERON:0018303	75.43	gold quality
rectum	UBERON:0001052	74.91	gold quality
stromal cell of endometrium	CL:0002255	73.87	gold quality
trabecular bone tissue	UBERON:0002483	73.87	gold quality
right hemisphere of cerebellum	UBERON:0014890	73.66	gold quality
cerebellar hemisphere	UBERON:0002245	73.23	gold quality
cerebellar cortex	UBERON:0002129	73.17	gold quality
tonsil	UBERON:0002372	73.05	gold quality
mucosa of transverse colon	UBERON:0004991	72.52	gold quality
apex of heart	UBERON:0002098	72.51	gold quality
bone marrow cell	CL:0002092	72.42	gold quality
bone marrow	UBERON:0002371	72.20	gold quality
cerebellum	UBERON:0002037	71.86	gold quality
metanephros cortex	UBERON:0010533	71.85	gold quality
gingival epithelium	UBERON:0001949	71.84	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.29
E-MTAB-6142	no	189.30

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

94 targeting DNA2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-570-3P	99.96	72.41	4910
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-551B-5P	99.96	71.28	3493

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 35)

• The purified human Dna2 enzyme contains intrinsic endonuclease and DNA-dependent ATPase activities, but is devoid of detectable DNA helicase activity. (PMID:16595799)
• hDna2 showed ATPase/helicase activity and 5’-3’ exo-endonuclease as well as 3’-5’ exo-endonuclease activity, indicating that its biochemical properties are very similar to yeast DNA2. (PMID:16595800)
• report here two novel activities of both the yeast and human Dna2 helicase/nuclease protein: single strand annealing and ATP-independent strand exchange on short duplexes (PMID:17032657)
• Replication protein A stimulates the 5’- to 3’-nuclease activity of Dna2 and inhibits the 3’- to 5’-exo/endonuclease activity of Dna2. (PMID:18593712)
• studies illustrate an evolutionarily diversified role of hDNA2 in mitochondrial DNA replication and repair in a mammalian system. (PMID:18995831)
• Data indicate that hDna2 is similar to its yeast counterpart and is a new addition to the growing list of proteins that participate in both nuclear and mitochondrial DNA maintenance. (PMID:19487465)
• Acetylation of Dna2 endonuclease/helicase and flap endonuclease 1 by p300 promotes DNA stability by creating long flap intermediates. (PMID:20019387)
• reviews the evidence for the dynamic design of Okazaki fragment processing and the roles of Dna2 and its interacting partners in carrying out this design. [REVIEW] (PMID:20131965)
• A characterization of the substrate specificities influencing hDna2 binding and cleavage functions and the sequential interaction of hFEN1 and hDna2 on Okazaki fragment intermediates. (PMID:22570407)
• analysis of Okazaki fragment processing-independent role for human Dna2 enzyme during DNA replication (PMID:22570476)
• DNA2 interacts with FANCD2, and cisplatin induces FANCD2 ubiquitylation even in the absence of DNA2. (PMID:22987153)
• These results implicate human DNA2 and the long-patch base-excision repair pathway in the pathogenesis of adult-onset disorders of mtDNA maintenance. (PMID:23352259)
• The suppression of FANCD2(-/-) by DNA2 knockdowns suggests that DNA2 and FANCD2 also have antagonistic roles: in the absence of FANCD2, DNA2 somehow corrupts repair. (PMID:24626199)
• WRN and BLM act epistatically with DNA2 to promote the long-range resection of double strand break ends in human cells. (PMID:25122754)
• DNA2 stimulates the helicase activity of BLM. (PMID:25200081)
• depletion of DNA2 in cells reduces proliferation, addition of estrogen restores proliferation. cells responding to estrogen will proliferate despite impaired in DNA2 activity, potentially promoting genomic instability and triggering cancer development. (PMID:25238049)
• EXO1, MRE11, and CtIP are not involved in the same mechanism of reversed fork processing, whereas human RECQ1 limits DNA2 activity by preventing extensive nascent strand degradation. (PMID:25733713)
• BRCA1 and CtIP contribute to DSB resection by recruiting Dna2 to damage sites, thus ensuring the robust DSB resection necessary for efficient homologous recombination. (PMID:25909997)
• The authors show that the helicase of hDNA2 functionally integrates with BLM or WRN helicases to promote double-stranded DNA degradation by forming a heterodimeric molecular machine. This collectively suggests that the human DNA2 motor promotes the enzyme’s capacity to degrade double-stranded DNA in conjunction with BLM or WRN and thus promote the repair of broken DNA. (PMID:27612385)
• the motor of DNA2 functions as a ssDNA translocase to promote degradation of 5’-terminated DNA. (PMID:28336515)
• This review mainly encompasses the key functions of DNA2 in human cells with various aspects, especially focusing on the genome integrity, and also generalizes the recent insights to the mechanisms related to the occurrence of cancer and other diseases potentially linked to the mutations in DNA2. (PMID:28903076)
• Here, the authors show that DNA2 binds preferentially to centromeric DNA. The nuclease and helicase activities of DNA2 are both essential for resolution of DNA structural obstacles to facilitate DNA replication fork movement. (PMID:29773570)
• TNF receptor associated factor 6 (TRAF6)-mediated DNA replication helicase/nuclease 2 (hDNA2) ubiquitination activates DNA repair pathways to maintain nuclear genome integrity. (PMID:31216032)
• Multiple roles of DNA2 nuclease/helicase in DNA metabolism, genome stability and human diseases have been described. (Review) (PMID:31754720)
• Study revealed that phosphorylated CtIP (pCtIP) dramatically stimulates the motor activity of DNA2. This accelerates degradation of RPA-coated ssDNA by DNA2, showing the need for the motor activity of DNA2 to facilitate resection. CtIP is thus a cofactor not only of MRE11, but also of DNA2, and domains of CtIP required for the stimulation of MRE11-RAD50-NBS1 (MRN) complex and DNA2 are physically separate. (PMID:32241893)
• The iron-sulphur cluster in human DNA2 is required for all biochemical activities of DNA2. (PMID:32576938)
• Limiting homologous recombination at stalled replication forks is essential for cell viability: DNA2 to the rescue. (PMID:32909097)
• Increased Expression of DNA2 Was Linked to Poor Prognosis in Breast Cancer. (PMID:33574966)
• Up-regulation of DNA2 results in cell proliferation and migration in endometriosis. (PMID:34047877)
• The nuclease activity of DNA2 promotes exonuclease 1-independent mismatch repair. (PMID:35300981)
• Estrogen upregulates DNA2 expression through the PI3K-AKT pathway in endometrial carcinoma. (PMID:36916001)
• FANCD2 and RAD51 recombinase directly inhibit DNA2 nuclease at stalled replication forks and FANCD2 acts as a novel RAD51 mediator in strand exchange to promote genome stability. (PMID:37526271)
• Targeting DNA2 overcomes metabolic reprogramming in multiple myeloma. (PMID:38331987)
• EXO1 and DNA2-mediated ssDNA gap expansion is essential for ATR activation and to maintain viability in BRCA1-deficient cells. (PMID:38721777)
• USP50 suppresses alternative RecQ helicase use and deleterious DNA2 activity during replication. (PMID:39284827)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
mus_musculus	Dna2	ENSMUSG00000036875
rattus_norvegicus	Dna2	ENSRNOG00000071263
drosophila_melanogaster	CG6701	FBGN0033889
drosophila_melanogaster	Mov10	FBGN0034187
caenorhabditis_elegans	Y106G6D.5	WBGENE00014965
caenorhabditis_elegans	sosi-1	WBGENE00016565
caenorhabditis_elegans	eri-7	WBGENE00016566

Paralogs (10): UPF1 (ENSG00000005007), AQR (ENSG00000021776), MOV10L1 (ENSG00000073146), SETX (ENSG00000107290), ZNFX1 (ENSG00000124201), HELZ2 (ENSG00000130589), IGHMBP2 (ENSG00000132740), MOV10 (ENSG00000155363), CT55 (ENSG00000169551), HELZ (ENSG00000198265)

Protein

Protein identifiers

DNA replication ATP-dependent helicase/nuclease DNA2 — P51530 (reviewed: P51530)

Alternative names: DNA replication ATP-dependent helicase-like homolog

All UniProt accessions (4): P51530, F8VPM6, F8VR31, H0Y455

UniProt curated annotations — full annotation on UniProt →

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.

Subunit / interactions. Interacts with BLM and WDHD1.

Subcellular location. Nucleus. Mitochondrion.

Post-translational modifications. 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.

Disease relevance. 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. The disease is caused by variants affecting the gene represented in this entry. 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 intellectual disability. The disease is caused by variants affecting the gene represented in this entry. Rothmund-Thomson syndrome 4 (RTS4) [MIM:620819] 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.

Cofactor. Binds 1 [4Fe-4S] cluster.

Similarity. Belongs to the DNA2/NAM7 helicase family.

Isoforms (4)

UniProt ID	Names	Canonical?
P51530-1	1	yes
P51530-2	2
P51530-3	3
P51530-4	4

RefSeq proteins (1): NP_001073918* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011604	PDDEXK-like_dom_sf	Homologous_superfamily
IPR014808	DNA_replication_fac_Dna2_N	Domain
IPR026851	Dna2/JHS1_DEXXQ-box	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR041677	DNA2/NAM7_AAA_11	Domain
IPR041679	DNA2/NAM7-like_C	Domain
IPR047187	SF1_C_Upf1	Domain
IPR048459	DNA2_Rift	Domain
IPR051827	Cas4_exonuclease	Family

Pfam: PF08696, PF13086, PF13087, PF21123

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (25 total): sequence variant 9, binding site 5, splice variant 4, region of interest 2, mutagenesis site 2, chain 1, sequence conflict 1, helix 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5EAY	X-RAY DIFFRACTION	1.55

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51530-F1	87.82	0.61

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (5): 136; 393; 396; 402; 648–655

Mutagenesis-validated functional residues (2):

Position	Phenotype
277	abolishes ability to resect dna in present of blm.
654	abolishes ability to unwind dna, while it does not affect ability to resect dna.

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-174437	Removal of the Flap Intermediate from the C-strand
R-HSA-5685938	HDR through Single Strand Annealing (SSA)
R-HSA-5685942	HDR through Homologous Recombination (HRR)
R-HSA-5693554	Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)
R-HSA-5693568	Resolution of D-loop Structures through Holliday Junction Intermediates
R-HSA-5693579	Homologous DNA Pairing and Strand Exchange
R-HSA-5693607	Processing of DNA double-strand break ends
R-HSA-5693616	Presynaptic phase of homologous DNA pairing and strand exchange
R-HSA-6804756	Regulation of TP53 Activity through Phosphorylation
R-HSA-69166	Removal of the Flap Intermediate
R-HSA-69473	G2/M DNA damage checkpoint
R-HSA-9701192	Defective homologous recombination repair (HRR) due to BRCA1 loss of function
R-HSA-9704331	Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function
R-HSA-9704646	Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function
R-HSA-9709570	Impaired BRCA2 binding to RAD51
R-HSA-9709603	Impaired BRCA2 binding to PALB2

MSigDB gene sets: 519 (showing top): GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, GOBP_CHROMOSOME_ORGANIZATION, MODULE_97, REACTOME_DNA_REPLICATION, GOBP_POSITIVE_REGULATION_OF_DNA_REPLICATION, GOMF_ENDONUCLEASE_ACTIVITY, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_CELL_CYCLE_DNA_REPLICATION, GOMF_NUCLEASE_ACTIVITY, REACTOME_G2_M_DNA_DAMAGE_CHECKPOINT, GOBP_MITOCHONDRIAL_DNA_METABOLIC_PROCESS, MORF_BRCA1, MORF_ATRX, GOBP_DNA_STRAND_ELONGATION_INVOLVED_IN_DNA_REPLICATION, GOBP_CELL_CYCLE_PHASE_TRANSITION

GO Biological Process (18): DNA replication checkpoint signaling (GO:0000076), telomere maintenance (GO:0000723), DNA double-strand break processing (GO:0000729), DNA replication (GO:0006260), mitochondrial DNA replication (GO:0006264), base-excision repair (GO:0006284), telomere maintenance via semi-conservative replication (GO:0032201), DNA geometric change (GO:0032392), DNA replication, Okazaki fragment processing (GO:0033567), DNA replication, removal of RNA primer (GO:0043137), mitochondrial DNA repair (GO:0043504), positive regulation of DNA replication (GO:0045740), replication fork reversal (GO:0071932), t-circle formation (GO:0090656), mitotic telomere maintenance via semi-conservative replication (GO:1902990), DNA metabolic process (GO:0006259), DNA repair (GO:0006281), DNA damage response (GO:0006974)

GO Molecular Function (19): DNA binding (GO:0003677), DNA helicase activity (GO:0003678), RNA binding (GO:0003723), helicase activity (GO:0004386), nuclease activity (GO:0004518), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), 5’-flap endonuclease activity (GO:0017108), single-stranded DNA helicase activity (GO:0017116), deoxyribonuclease (pyrimidine dimer) activity (GO:0033892), 5’-3’ DNA helicase activity (GO:0043139), metal ion binding (GO:0046872), 4 iron, 4 sulfur cluster binding (GO:0051539), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), endonuclease activity (GO:0004519), protein binding (GO:0005515), hydrolase activity (GO:0016787), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (7): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial nucleoid (GO:0042645), gamma DNA polymerase complex (GO:0005760)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	3
Resolution of D-Loop Structures	2
Defective homologous recombination repair (HRR) due to PALB2 loss of function	2
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	2
Processive synthesis on the C-strand of the telomere	1
HDR through Homologous Recombination (HRR)	1
Homologous DNA Pairing and Strand Exchange	1
Regulation of TP53 Activity	1
Processive synthesis on the lagging strand	1
G2/M Checkpoints	1
Diseases of DNA Double-Strand Break Repair	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	5
mitochondrion	3
mitochondrial DNA metabolic process	2
DNA repair	2
DNA replication	2
nucleic acid binding	2
catalytic activity, acting on a nucleic acid	2
ATP-dependent activity	2
DNA helicase activity	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
mitochondrial matrix	2
DNA integrity checkpoint signaling	1
telomere organization	1
double-strand break repair	1
5’-3’ DNA exonuclease activity	1
DNA biosynthetic process	1
DNA-templated DNA replication	1
telomere maintenance	1
cell cycle process	1
nuclear DNA replication	1
DNA conformation change	1
lagging strand elongation	1
RNA catabolic process	1
regulation of DNA replication	1
positive regulation of DNA metabolic process	1
replication fork processing	1
formation of extrachromosomal circular DNA	1
telomere maintenance via telomere trimming	1
mitotic cell cycle	1
telomere maintenance via semi-conservative replication	1
mitotic cell cycle process	1
nucleic acid metabolic process	1
DNA damage response	1
cellular response to stress	1
helicase activity	1
ATP-dependent activity, acting on DNA	1
nucleic acid conformation isomerase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1

Protein interactions and networks

STRING

2632 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DNA2	TOP3A	Q13472	995
DNA2	WRN	Q14191	994
DNA2	EXO1	Q9UQ84	988
DNA2	RMI1	Q9H9A7	987
DNA2	FEN1	P39748	975
DNA2	BLM	P54132	919
DNA2	RAD51	Q06609	916
DNA2	RBBP8	Q99708	912
DNA2	WDHD1	O75717	885
DNA2	RECQL	P46063	866
DNA2	LIG1	P18858	856
DNA2	TWNK	Q96RR1	843
DNA2	PIF1	Q9H611	841
DNA2	XRCC6	P12956	829
DNA2	ATM	Q13315	825

IntAct

43 interactions, top by confidence:

A	B	Type	Score
DBF4	CDC7	psi-mi:“MI:0914”(association)	0.890
SMARCD1	ARID1A	psi-mi:“MI:0914”(association)	0.790
DNAJC7	PLD2	psi-mi:“MI:0914”(association)	0.640
PRKCSH	AURKA	psi-mi:“MI:0914”(association)	0.530
NRBP1	TBC1D4	psi-mi:“MI:0914”(association)	0.530
CDR2	IGSF3	psi-mi:“MI:0914”(association)	0.530
DNA2	CIAO1	psi-mi:“MI:0914”(association)	0.530
DNA2	WDHD1	psi-mi:“MI:0915”(physical association)	0.400
DNA2	PLEC	psi-mi:“MI:0915”(physical association)	0.400
DNA2	TARSL2	psi-mi:“MI:0914”(association)	0.350
CDR2	IGSF3	psi-mi:“MI:0914”(association)	0.350
rep	TBKBP1	psi-mi:“MI:0914”(association)	0.350
CUL4A	DDX39A	psi-mi:“MI:0914”(association)	0.350
CUL4B	GGTLC3	psi-mi:“MI:0914”(association)	0.350
DCAF4	IGLL5	psi-mi:“MI:0914”(association)	0.350
FKBP5	IFT56	psi-mi:“MI:0914”(association)	0.350
PTGES3	KIFBP	psi-mi:“MI:0914”(association)	0.350
PPP4R1L	IFT56	psi-mi:“MI:0914”(association)	0.350
DNA2	TARS3	psi-mi:“MI:0914”(association)	0.350
CFAP184	TARS3	psi-mi:“MI:0914”(association)	0.350
DUSP16	MEIOC	psi-mi:“MI:0914”(association)	0.350
TRIM52	MEIOC	psi-mi:“MI:0914”(association)	0.350
PTGES3	SBNO1	psi-mi:“MI:0914”(association)	0.350
DNAJA2	DENND11	psi-mi:“MI:0914”(association)	0.350
AVIL	DCTN6	psi-mi:“MI:0914”(association)	0.350
MRPS7	CALU	psi-mi:“MI:0914”(association)	0.350
TTC12	DNA2	psi-mi:“MI:0914”(association)	0.350

BioGRID (117): DNA2 (Affinity Capture-RNA), DNA2 (Affinity Capture-RNA), DNA2 (Affinity Capture-RNA), DNA2 (Affinity Capture-MS), DNA2 (Affinity Capture-Western), DNA2 (Biochemical Activity), DNA2 (Reconstituted Complex), DNA2 (Affinity Capture-Western), EP300 (Affinity Capture-Western), FEN1 (Affinity Capture-Western), DNA2 (Affinity Capture-MS), DNA2 (Affinity Capture-MS), DNA2 (Affinity Capture-MS), RBBP8 (Affinity Capture-Western), RBBP8 (Reconstituted Complex)

ESM2 similar proteins: A2AV36, A2VD33, A4QN59, A4QP75, A6QQV6, B0WSX1, B3MZN7, B4PYH5, B8A5G9, D3ZG52, D9IVE5, E1BMP7, F1QCV2, O95470, P51530, Q14CH1, Q16GH0, Q16P90, Q28CZ7, Q2VPA6, Q32PX9, Q3T0H0, Q3TZM9, Q4KLT3, Q4V7D6, Q502I6, Q58E95, Q5U4E8, Q5U534, Q5ZIB9, Q5ZKG3, Q655R6, Q6NTR1, Q6P4Z6, Q6PCI6, Q6ZQJ5, Q8AWD2, Q8BIP0, Q8GWT4, Q8LGM7

Diamond homologs: A0A1P8ASY1, A2AKX3, D3ZG52, E1BMP7, E9QAM5, O94387, P30771, P38859, P38935, P51530, Q5ZKG3, Q6ZQJ5, Q7Z333, Q8QHA5, Q92355, Q92900, Q98TR3, Q9EPU0, Q9HEH1, Q9URU2, B6SFA4, F1RCY6, K0E4D9, O76512, O94247, P39369, Q00416, Q0VGT4, Q54I89, Q86AS0, Q86YA3, Q8GYD9, Q9BXT6, Q9FJR0, Q9VYS3, F6QXW0, Q09820, Q57568, P23249, P32644

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CHEK2	“up-regulates activity”	DNA2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

1044 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	11
Uncertain significance	556
Likely benign	322
Benign	80

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1710081	NM_001080449.3(DNA2):c.588-2214A>G	Pathogenic
1710084	NC_000010.11:g.68413754_68420303del	Pathogenic
1710085	NM_001080449.3(DNA2):c.2208+2456_2403-18del	Pathogenic
1710086	NM_001080449.3(DNA2):c.442-768_587+648del	Pathogenic
3235127	NM_001080449.3:c.1764-38_1764-37insGAACCTCAAACAGCCAGGAGCAGCTGGAATGCAGGCCTTTCACTCCACTTTTC	Pathogenic
3235129	NM_001080449.3(DNA2):c.1963A>G (p.Thr655Ala)	Pathogenic
1710082	NM_001080449.3(DNA2):c.143T>C (p.Leu48Pro)	Likely pathogenic
2907397	NM_001080449.3(DNA2):c.74+4A>C	Likely pathogenic
3342590	NM_001080449.3(DNA2):c.1057+1G>A	Likely pathogenic
424949	NM_001080449.3(DNA2):c.186_187dup (p.Glu63fs)	Likely pathogenic
4531504	NM_001080449.3(DNA2):c.441+1G>A	Likely pathogenic
4813803	NM_001080449.3(DNA2):c.1501C>T (p.Gln501Ter)	Likely pathogenic
4845251	NM_001080449.3(DNA2):c.2305C>T (p.Gln769Ter)	Likely pathogenic
503930	NM_001080449.3(DNA2):c.73_74+10del	Likely pathogenic
522960	NM_001080449.3(DNA2):c.3014C>T (p.Thr1005Ile)	Likely pathogenic
807407	NM_001080449.3(DNA2):c.1919C>T (p.Ser640Leu)	Likely pathogenic
817733	NM_001080449.3(DNA2):c.1817del (p.Tyr606fs)	Likely pathogenic

SpliceAI

3867 predictions. Top by Δscore:

Variant	Effect	Δscore
10:68419076:A:AC	donor_gain	1.0000
10:68419077:C:CC	donor_gain	1.0000
10:68419084:C:A	donor_gain	1.0000
10:68419088:T:A	donor_gain	1.0000
10:68419116:TCG:T	donor_gain	1.0000
10:68422271:C:CA	donor_gain	1.0000
10:68422425:TTTTA:T	acceptor_gain	1.0000
10:68422426:TTTA:T	acceptor_gain	1.0000
10:68422430:C:CC	acceptor_gain	1.0000
10:68424615:T:TA	donor_gain	1.0000
10:68430434:A:AC	donor_gain	1.0000
10:68430435:C:CC	donor_gain	1.0000
10:68430435:CTTGA:C	donor_gain	1.0000
10:68431860:A:AC	donor_gain	1.0000
10:68431861:C:CC	donor_gain	1.0000
10:68431873:T:C	donor_gain	1.0000
10:68432204:AC:A	donor_gain	1.0000
10:68432205:CC:C	donor_gain	1.0000
10:68432507:GTTT:G	acceptor_gain	1.0000
10:68432508:TTT:T	acceptor_gain	1.0000
10:68432509:TT:T	acceptor_gain	1.0000
10:68432509:TTCTA:T	acceptor_loss	1.0000
10:68432511:C:CC	acceptor_gain	1.0000
10:68432511:CT:C	acceptor_loss	1.0000
10:68432512:T:A	acceptor_loss	1.0000
10:68443107:CTGCT:C	acceptor_gain	1.0000
10:68459102:A:AC	donor_gain	1.0000
10:68459103:C:CC	donor_gain	1.0000
10:68459103:CA:C	donor_gain	1.0000
10:68465665:A:AC	donor_gain	1.0000

AlphaMissense

7028 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:68416791:A:G	L1011P	0.999
10:68419090:C:G	G971R	0.999
10:68419090:C:T	G971R	0.999
10:68422523:T:A	R828S	0.999
10:68422523:T:G	R828S	0.999
10:68422524:C:A	R828I	0.999
10:68422524:C:G	R828T	0.999
10:68422525:T:C	R828G	0.999
10:68422743:C:A	G786W	0.999
10:68422809:C:G	A764P	0.999
10:68430597:C:G	D683H	0.999
10:68430616:G:C	S676R	0.999
10:68430616:G:T	S676R	0.999
10:68430618:T:G	S676R	0.999
10:68431884:T:A	K654I	0.999
10:68431887:C:T	G653E	0.999
10:68431894:C:A	G651W	0.999
10:68431955:C:A	Q630H	0.999
10:68431955:C:G	Q630H	0.999
10:68416805:T:A	R1006S	0.998
10:68416805:T:G	R1006S	0.998
10:68416806:C:A	R1006I	0.998
10:68416806:C:G	R1006T	0.998
10:68419089:C:T	G971E	0.998
10:68419091:T:A	Q970H	0.998
10:68419091:T:G	Q970H	0.998
10:68422385:A:G	L846P	0.998
10:68422521:A:G	M829T	0.998
10:68422583:G:C	S808R	0.998
10:68422583:G:T	S808R	0.998

dbSNP variants (sampled 300 via entrez): RS1000004376 (10:68439538 C>T), RS1000097065 (10:68422981 T>G), RS1000101177 (10:68464458 T>C,G), RS1000134115 (10:68472703 G>A,C), RS1000238017 (10:68433878 G>A), RS1000265386 (10:68457809 T>C), RS1000286160 (10:68445183 G>A,T), RS1000331511 (10:68452427 G>C), RS1000358364 (10:68427219 T>A,C), RS1000418900 (10:68426831 T>C,G), RS1000608581 (10:68418463 C>T), RS1000642041 (10:68461164 T>C), RS1000678800 (10:68416847 T>C), RS1000760895 (10:68414173 C>A,G,T), RS1000764706 (10:68467207 G>C)

Disease associations

OMIM: gene MIM:601810 | disease phenotypes: MIM:615156, MIM:615807, MIM:262400, MIM:268400, MIM:620819, MIM:117000

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial DNA deletion syndrome with progressive myopathy	Strong	Autosomal dominant
Seckel syndrome 8	Strong	Autosomal recessive
Rothmund-Thomson syndrome type 4	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
mitochondrial disease	Moderate	AD

Mondo (8): mitochondrial DNA deletion syndrome with progressive myopathy (MONDO:0014062), Seckel syndrome 8 (MONDO:0014350), isolated growth hormone deficiency type IA (MONDO:0009876), Rothmund-Thomson syndrome (MONDO:0010002), Rothmund-Thomson syndrome type 4 (MONDO:0970950), long QT syndrome (MONDO:0002442), congenital myopathy (MONDO:0019952), microcephaly (MONDO:0001149)

Orphanet (6): DNA2-related mitochondrial DNA deletion syndrome (Orphanet:352470), Seckel syndrome (Orphanet:808), Isolated growth hormone deficiency type IA (Orphanet:231662), Non-acquired isolated growth hormone deficiency (Orphanet:631), Rothmund-Thomson syndrome (Orphanet:2909), Congenital myopathy (Orphanet:97245)

HPO phenotypes

102 total (30 of 102 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000054	Micropenis
HP:0000086	Ectopic kidney
HP:0000252	Microcephaly
HP:0000275	Narrow face
HP:0000347	Micrognathia
HP:0000363	Abnormal earlobe morphology
HP:0000387	Absent earlobe
HP:0000444	Convex nasal ridge
HP:0000490	Deeply set eye
HP:0000494	Downslanted palpebral fissures
HP:0000501	Glaucoma
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000568	Microphthalmia
HP:0000590	Progressive external ophthalmoplegia
HP:0000597	Ophthalmoparesis
HP:0000648	Optic atrophy
HP:0000659	Peters anomaly
HP:0000682	Abnormal dental enamel morphology
HP:0000684	Delayed eruption of teeth
HP:0000716	Depression
HP:0000821	Hypothyroidism
HP:0000926	Platyspondyly
HP:0000938	Osteopenia
HP:0000992	Cutaneous photosensitivity
HP:0001029	Poikiloderma
HP:0001249	Intellectual disability

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90020028_77	Hip circumference adjusted for BMI	4.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D011038	Rothmund-Thomson Syndrome	C16.131.831.775; C16.320.850.765; C16.614.760; C17.800.804.775; C17.800.827.775; C18.452.284.760
C537404	Pituitary dwarfism 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523236 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

47 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, decreases expression, affects cotreatment, increases abundance	4
Valproic Acid	decreases expression	3
Cyclosporine	decreases expression	3
bisphenol A	decreases expression, decreases methylation	2
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Benzo(a)pyrene	increases expression, increases methylation	2
Cannabidiol	decreases expression, increases expression	2
Oxygen	decreases expression	2
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
arsenite	affects binding, decreases reaction	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
brequinar	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CPG-oligonucleotide	decreases expression	1
abrine	decreases expression	1
jinfukang	decreases expression	1
incobotulinumtoxinA	decreases expression	1
picoxystrobin	increases expression	1
Dasatinib	decreases expression	1
Resveratrol	decreases expression	1
Temozolomide	affects response to substance	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Azathioprine	decreases expression	1
Calcitriol	affects cotreatment, decreases expression	1

ChEMBL screening assays

23 unique, capped per target: 23 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4418059	Binding	Inhibition of DNA2 in HU-treated human A549 cells assessed as inhibition of DNA replication fork restart by measuring restarting forks levels at 20 uM pre-incubated for 40 mins followed by incubation with 250 uM C1dU for 40 mins by DNA fibe	DNA2 inhibitors for cancer treatment

Clinical trials (associated diseases)

98 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT01304407	Not specified	COMPLETED	Calcium Absorption in Patients With Rothmund-Thomson Syndrome
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT05906732	PHASE1/PHASE2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy
NCT00588965	Not specified	COMPLETED	Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects
NCT01705925	Not specified	COMPLETED	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome
NCT01903564	Not specified	COMPLETED	Fetal and Neonatal Magnetophysiology
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT02425189	Not specified	COMPLETED	The Canadian National Long QT Syndrome Registry
NCT02439645	Not specified	TERMINATED	A Registry to Determine the Clinical and Genetic Risk Factors for Torsade De Pointes
NCT02439658	Not specified	UNKNOWN	Genetics of QT Prolongation With Antiarrhythmics
NCT02549664	Not specified	COMPLETED	Exercise in Genetic Cardiovascular Conditions
NCT02581241	Not specified	COMPLETED	Abnormal QT-Response to the Sudden Tachycardia Provoked by Standing in Individuals With Drug-induced Long QT Syndrome
NCT02680080	Not specified	COMPLETED	Effect of Grapefruit on QT Interval in Healthy Volunteers and Patients With Congenital Long QT Syndrome
NCT02775513	Not specified	UNKNOWN	Metabolism of Patients With Genetically Caused Cardiac Arrhythmia
NCT02814981	Not specified	UNKNOWN	Hydroxyzine and Risk of Prolongation of QT Interval
NCT02876380	Not specified	COMPLETED	Prospective Identification of Long QT Syndrome in Fetal Life
NCT03182777	Not specified	COMPLETED	Safety of Local Dental Anesthesia in Patients With Cardiac Channelopathies
NCT03544918	Not specified	COMPLETED	Prevalence of Congenital Long QT Syndrome and Acquired QT Prolongation in a Hospital Cohort