POLA1: DNA Polymerase Alpha 1, Catalytic Subunit
Essential Replicative DNA Polymerase and Key Player in DNA Repair and Cell Cycle Regulation
Gene Information Card
| Symbol | POLA1 |
|---|---|
| Full Name | DNA Polymerase Alpha 1, Catalytic Subunit |
| Gene Type | Protein coding |
| Chromosomal Location | Xp22.11-p21.3 |
| NCBI Gene ID | 5422 ncbi.nlm.nih.gov/gene/5422 |
| Ensembl ID | ENSG00000186868 |
| UniProt ID | P09884 |
| OMIM ID | 312040 |
| HGNC ID | 9173 |
| Aliases | POLA, p180, NSX, XAPC |
Description
POLA1 encodes the catalytic subunit (p180) of DNA polymerase alpha, a heterotetrameric enzyme essential for the initiation of DNA replication. The polymerase alpha complex (Pol α) possesses both primase and DNA polymerase activities, synthesizing short RNA-DNA primers on the lagging strand during replication. POLA1 is also involved in DNA repair pathways and cell cycle checkpoint control. Mutations in POLA1 are associated with X-linked intellectual disability and Van Esch-O'Driscoll syndrome, and somatic alterations are implicated in various cancers.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| X-linked intellectual disability with or without seizures (Van Esch-O'Driscoll syndrome) | Loss-of-function mutations impair DNA replication and repair, leading to genomic instability and neurodevelopmental defects. | ClinVar, OMIM |
| Primary microcephaly | Defects in POLA1 disrupt neural progenitor cell proliferation due to replication stress. | OMIM, PubMed |
| Colorectal cancer | Somatic mutations and copy number alterations in POLA1 contribute to replication stress and tumorigenesis. | COSMIC, PubMed |
| Breast cancer | Overexpression and mutations in POLA1 are associated with poor prognosis and genomic instability. | COSMIC, PubMed |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 15.2 | High |
| Bone marrow | 12.8 | High |
| Lymph node | 11.5 | High |
| Brain (cerebellum) | 8.3 | Medium |
| Liver | 6.1 | Medium |
| Heart | 4.7 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa | 18.5 | Cervical cancer cell line; high expression |
| HEK293 | 14.2 | Embryonic kidney; moderate-high expression |
| K562 | 16.1 | Leukemia cell line; high expression |
| MCF7 | 12.3 | Breast cancer; moderate expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1799G>A (p.Arg600His) | Missense | Rare | Reduced polymerase activity; associated with X-linked intellectual disability |
| c.2542C>T (p.Arg848Trp) | Missense | Rare | Impaired primase interaction; Van Esch-O'Driscoll syndrome |
| c.3310_3311del (p.Leu1104fs) | Frameshift | Very rare | Loss of function; severe neurodevelopmental phenotype |
| c.1465A>G (p.Asn489Asp) | Missense | Somatic (0.2% in COSMIC) | Possible gain-of-function in colorectal cancer |
Mutation functional classification
Loss of Function (LOF)
Missense and frameshift mutations that reduce or abolish DNA polymerase activity, leading to replication stress and genomic instability. Associated with X-linked intellectual disability and microcephaly.
Gain of Function (GOF)
Rare somatic missense mutations (e.g., p.Asn489Asp) may increase processivity or alter substrate specificity, potentially contributing to oncogenesis.
Dominant Negative (DN)
Not well documented; however, certain missense mutations may interfere with complex assembly, exerting a dominant-negative effect on Pol α function.
View complete mutation data：
Gene Ontology (GO)
| • DNA replication initiation | • DNA primase activity |
| • DNA-directed DNA polymerase activity | • nucleus |
| • nucleoplasm | • protein binding |
| • metal ion binding | • cell cycle |
| • DNA repair |
Pathways
• DNA replication (KEGG: hsa03030)
• Cell cycle (KEGG: hsa04110)
• Base excision repair (KEGG: hsa03410)
• Mismatch repair (KEGG: hsa03430)
Protein Summary
POLA1 encodes the 180 kDa catalytic subunit of DNA polymerase alpha, a B-family DNA polymerase. The protein contains an N-terminal domain involved in primase interaction, a central polymerase domain, and a C-terminal domain required for complex stability. It functions as part of the Pol α-primase complex, synthesizing RNA-DNA primers for Okazaki fragment initiation. The protein is essential for cell proliferation and is highly expressed in tissues with rapid cell turnover. Post-translational modifications include phosphorylation, which regulates activity during the cell cycle.
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