TOP3A: DNA Topoisomerase III Alpha
A key enzyme in DNA replication, recombination, and repair, with implications in Bloom syndrome and cancer susceptibility.
Gene Information Card
| Symbol | TOP3A |
|---|---|
| Full Name | DNA topoisomerase III alpha |
| Gene Type | protein-coding |
| Chromosomal Location | 17p11.2 |
| NCBI Gene ID | 7156 ncbi.nlm.nih.gov/gene/7156 |
| Ensembl ID | ENSG00000177302 |
| UniProt ID | Q13472 |
| OMIM ID | 601241 |
| HGNC ID | 11992 |
| Aliases | TOP3, ZGRF7 |
Description
TOP3A encodes DNA topoisomerase III alpha, a type IA topoisomerase that regulates DNA topology by transiently breaking and rejoining single-stranded DNA. It is essential for resolving recombination intermediates, maintaining genomic stability, and preventing sister chromatid exchanges. Mutations in TOP3A are associated with Bloom syndrome-like disorders and increased cancer risk.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Bloom syndrome-like disorder | Loss-of-function mutations impair DNA decatenation and recombination repair, leading to genomic instability and growth retardation. | OMIM #601241; ClinVar |
| Breast cancer susceptibility | Rare missense variants may disrupt topoisomerase activity, increasing DNA damage accumulation. | COSMIC; NCBI Gene |
| Acute myeloid leukemia | Somatic mutations in TOP3A contribute to clonal hematopoiesis and leukemogenesis. | COSMIC |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 12.5 | High |
| Bone marrow | 8.3 | Medium |
| Lymph node | 6.1 | Medium |
| Brain | 4.2 | Low |
| Liver | 3.8 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| K562 (leukemia) | 10.2 | High expression |
| HeLa (cervical) | 7.5 | Medium expression |
| HepG2 (liver) | 4.0 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.238G>A (p.Glu80Lys) | Missense | <0.01% | Reduced catalytic activity; associated with Bloom-like syndrome |
| c.1120C>T (p.Arg374Trp) | Missense | 0.02% | Impaired DNA binding; linked to breast cancer |
| c.1465_1466del (p.Leu489fs) | Frameshift | Rare | Loss of function; genomic instability |
Mutation functional classification
Loss of Function (LOF)
Frameshift and nonsense mutations that truncate the protein or disrupt the active site tyrosine (e.g., p.Tyr365*) lead to complete loss of topoisomerase activity, causing genomic instability and Bloom syndrome-like phenotypes.
Gain of Function (GOF)
No confirmed gain-of-function mutations reported for TOP3A.
Dominant Negative (DN)
Certain missense mutations (e.g., p.Glu80Lys) may produce a protein that interferes with wild-type TOP3A or its binding partners, impairing decatenation.
View complete mutation data：
Gene Ontology (GO)
| • DNA topoisomerase activity (GO:0003916) | • DNA binding (GO:0003677) |
| • DNA replication (GO:0006260) | • DNA recombination (GO:0006310) |
| • chromosome segregation (GO:0007059) |
Pathways
• Resolution of D-loop structures through Holliday junction intermediates
• BLM-TOP3A-RMI1-RMI2 (BTR) complex in homologous recombination
• Decatenation of newly replicated DNA
Protein Summary
TOP3A is a 1001-amino-acid type IA topoisomerase that forms a heterotetrameric complex with BLM helicase, RMI1, and RMI2 (BTR complex). It catalyzes the passage of single-stranded DNA through a transient break, resolving recombination intermediates and preventing sister chromatid exchanges. The protein is localized to the nucleus and is essential for maintaining genomic stability during DNA replication and repair.
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