PNKP: Polynucleotide Kinase 3'-Phosphatase
A key DNA repair enzyme in neurological and cancer contexts
Gene Information Card
| Symbol | PNKP |
|---|---|
| Full Name | Polynucleotide Kinase 3'-Phosphatase |
| Gene Type | Protein coding |
| Chromosomal Location | 19q13.33 |
| NCBI Gene ID | 11284 ncbi.nlm.nih.gov/gene/11284 |
| Ensembl ID | ENSG00000130829 |
| UniProt ID | Q96T60 |
| OMIM ID | 605610 |
| HGNC ID | 9154 |
| Aliases | PNK, MCSZ, PNKP1, PNKP2 |
Description
PNKP encodes a bifunctional enzyme with both 5'-DNA kinase and 3'-DNA phosphatase activities, essential for repairing single-strand breaks and processing DNA ends during base excision repair. Mutations in PNKP cause microcephaly, seizures, and developmental delay (MCSZ syndrome) and are implicated in cancer susceptibility.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Microcephaly, seizures, and developmental delay (MCSZ) | Loss-of-function mutations impair DNA repair, leading to neuronal apoptosis | OMIM #613402 |
| Ataxia-oculomotor apraxia 4 (AOA4) | Defective DNA repair in cerebellar neurons | OMIM #616267 |
| Breast cancer | Somatic mutations and reduced expression linked to genomic instability | COSMIC, ClinVar |
| Glioblastoma | Altered PNKP expression affects DNA repair capacity in tumors | COSMIC |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 12.5 | Medium |
| Testis | 8.3 | Medium |
| Liver | 6.1 | Low |
| Heart | 5.4 | Low |
| Kidney | 4.8 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK293 | 10.2 | High expression |
| HeLa | 8.7 | Moderate |
| SH-SY5Y | 9.1 | Neuronal model |
| MCF7 | 6.3 | Breast cancer line |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1250G>A (p.Arg417Gln) | Missense | Rare | Loss of phosphatase activity; MCSZ |
| c.1129C>T (p.Arg377Trp) | Missense | Rare | Impaired kinase activity; AOA4 |
| c.1393G>A (p.Glu465Lys) | Missense | Rare | Reduced DNA binding; MCSZ |
| c.458T>C (p.Leu153Pro) | Missense | Rare | Structural destabilization; MCSZ |
Mutation functional classification
Loss of Function (LOF)
Most MCSZ and AOA4 mutations reduce or abolish enzymatic activity, leading to defective DNA repair.
Gain of Function (GOF)
Not reported for PNKP.
Dominant Negative (DN)
Not established; mutations are typically recessive.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Base excision repair (Reactome R-HSA-73884)
• Nonhomologous end-joining (Reactome R-HSA-5693571)
• DNA double-strand break repair (KEGG hsa03450)
Protein Summary
PNKP is a 521-amino acid nuclear protein with an N-terminal forkhead-associated (FHA) domain and a C-terminal catalytic domain. It phosphorylates 5'-hydroxyl termini and dephosphorylates 3'-phosphate ends, generating ligatable ends for DNA repair. The enzyme interacts with XRCC1, XRCC4, and other repair factors.
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