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POLD1
DNA polymerase delta 1, catalytic subunit
The POLD1 gene provides instructions for making a subunit of DNA polymerase delta, a crucial enzyme involved in DNA replication and repair, particularly in correcting errors during DNA synthesis. The POLD1 gene encodes the catalytic subunit of DNA polymerase delta, an enzyme essential for maintaining the integrity of our genetic material.
POLD1 is located on the long (q) arm of chromosome 19, at band 19q13.33. Arm ratio per GRCh38 - banding schematic.
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Overview
The POLD1 gene, short for DNA polymerase delta 1, catalytic subunit, is fundamental to cellular health. It contains the blueprint for the primary catalytic subunit of DNA polymerase delta, an enzyme vital for DNA replication and repair mechanisms within the cell. This gene's proper function is essential for ensuring that genetic information is accurately copied and maintained through each cell division. Disruption to POLD1 can lead to errors accumulating in the DNA, potentially contributing to various health issues.
Inherited changes in the POLD1 gene are associated with an autosomal dominant inheritance pattern, meaning only one altered copy of the gene is sufficient to increase an individual's predisposition to certain conditions. Understanding the POLD1 gene is crucial for insights into cancer predisposition and inherited genetic syndromes, reflecting its critical role in genomic stability.
What the gene does
The protein encoded by the POLD1 gene, DNA polymerase delta 1, acts as the catalytic subunit of DNA polymerase delta (Pol δ). Pol δ is a multi-subunit enzyme complex that plays a central role in both DNA replication and DNA repair. During DNA replication, Pol δ is responsible for synthesising the lagging strand, performing highly accurate DNA synthesis. This process requires not only the addition of new DNA bases but also a crucial proofreading function to correct any mistakes made during synthesis.
Its 3'-5' exonuclease activity enables mispaired nucleotides to be removed immediately after they are added, significantly reducing the error rate of DNA replication. Beyond replication, POLD1 is also involved in various DNA repair pathways, including nucleotide excision repair and base excision repair, further cementing its importance in maintaining genomic stability. The proper functioning of POLD1 is paramount to prevent the accumulation of mutations, which can lead to cellular dysfunction or disease.
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Chromosome location
The POLD1 gene is located on chromosome 19, specifically at position 19q13.33. This locus refers to the long arm (q) of chromosome 19, within sub-band 33 of region 13. The precise location of this gene helps geneticists and researchers map its position relative to other genes on the chromosome and understand its contribution to the overall genetic landscape. While the exact number of exons can vary marginally based on transcript isoforms, POLD1 is a substantial gene encoding a protein of 1107 amino acids.
Protein structure
The POLD1 protein, the catalytic subunit of DNA polymerase delta, has a complex architecture critical for its function. An N-terminal Disordered region spans amino acids 1 to 34, which often facilitates protein-protein interactions and flexibility. Within this disordered region, a Nuclear localization signal is found between amino acids 4 and 19, which is crucial for directing the protein to its site of action within the nucleus. Towards the C-terminus, the protein features two significant motifs: a CysA-type Zinc finger (amino acids 1012-1029) and a CysB motif (amino acids 1058-1076). These Cys-type motifs are typically involved in structural stabilisation and may play a role in DNA binding or interaction with other protein subunits, critical for the enzyme's catalytic and proofreading activities.
Key variants
Genetic variations within the POLD1 gene can range from benign polymorphisms to pathogenic variants that impact protein function. Pathogenic variants can include missense changes, frameshift mutations, or deletions, all of which may impair the protein's ability to accurately replicate and repair DNA. Even subtle changes in critical regions of the POLD1 gene can diminish its proofreading capacity, leading to an increased rate of mutations accumulating in the genome. The effect of a specific variant often depends on its location within the gene and how it alters the resultant protein structure and function. Understanding these variants is key to assessing an individual's genetic predisposition to associated conditions.
Sample of pathogenic variants
8 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1421T>C | p.Leu474Pro | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1433G>A | p.Ser478Asn | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1809CTC[1] | p.Ser605del | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.365_377del | p.Val122fs | Pathogenic | ★☆☆☆ | Lipodystrophy - childhood onset |
c.3148del | p.Arg1050fs | Pathogenic | - | Carcinoma of pancreas |
c.1432A>C | p.Ser478Arg | Likely pathogenic | ★☆☆☆ | Hereditary cancer-predisposing syndrome |
c.1519C>T | p.Arg507Cys | Likely pathogenic | ★☆☆☆ | Colorectal cancer, susceptibility to, 10 |
c.3219C>G | p.Ser1073Arg | Likely pathogenic | - | Intellectual disability |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the POLD1 gene are primarily associated with an inherited condition known as Polymerase proofreading-associated polyposis. This condition is characterised by the development of multiple polyps in the gastrointestinal tract, particularly the colon, which can increase the risk of colorectal cancer. The autosomal dominant inheritance pattern means that individuals inheriting just one pathogenic variant in POLD1 from a parent have an increased likelihood of developing this disorder. The clinical presentation can vary, but typically involves an elevated risk of early-onset colorectal cancers and, in some cases, tumours in other organs.
- Polymerase proofreading-associated polyposis Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic POLD1 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The POLD1 gene is recognised within the NHS Genomic Medicine Service due to its clinical significance, particularly concerning cancer susceptibility. It is listed as 'green' on multiple NHS England PanelApp panels, indicating strong evidence for its association with specific conditions and its utility in clinical genetic testing. These panels include 'Adult solid tumours cancer susceptibility', 'Adult solid tumours for rare disease', and 'Colorectal cancer pertinent cancer susceptibility', reflecting its established role in cancer predisposition. Additionally, POLD1 is part of the 'Inherited polyposis and early onset colorectal cancer - germline testing' panel (R211), and panels related to diabetes such as 'Monogenic diabetes' (R141) and 'Severe insulin resistance and lipodystrophy syndromes' (R158), which highlights its broader clinical relevance.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining a healthy lifestyle is generally recommended for overall well-being, irrespective of one's genetic background. For individuals with an increased genetic predisposition to conditions like Polymerase proofreading-associated polyposis due to POLD1 variants, general health advice that might indirectly support gut health includes a balanced diet rich in fibre, regular physical activity, and avoiding excess consumption of red and processed meats. While these lifestyle choices are important for the general population in reducing cancer risk, there is no conclusive evidence that they can prevent the manifestation of genetically predisposed conditions or reverse the effects of POLD1 variants.
Supplement considerations
Currently, there is no conclusive scientific evidence to suggest that specific dietary supplements can prevent, treat, or reverse conditions associated with POLD1 gene variants. While some supplements are marketed for gut health or cancer prevention, these claims are often not supported by robust clinical trials in the context of specific genetic predispositions. Individuals considering any supplements should consult with a healthcare professional to discuss potential benefits, risks, and interactions with other medications. It is important to remember that supplements should not be used as a substitute for medical advice or prescribed treatments.
Frequently asked questions
What is the POLD1 gene?
The POLD1 gene provides instructions for making the catalytic subunit of DNA polymerase delta, an enzyme critical for accurate DNA replication and repair. It includes a proofreading function to correct errors during DNA synthesis.
What conditions are associated with POLD1 variants?
Pathogenic variants in the POLD1 gene are primarily associated with Polymerase proofreading-associated polyposis, an inherited condition characterised by increased risk of colorectal polyps and cancer.
How is POLD1 inherited?
Variants in the POLD1 gene are typically inherited in an autosomal dominant pattern. This means that a person needs to inherit only one copy of the altered gene from one parent to have an increased genetic predisposition to associated conditions.
What is the role of POLD1 in DNA repair?
Beyond its primary role in DNA replication, POLD1 also participates in several DNA repair pathways, including nucleotide excision repair and base excision repair. Its proofreading capability is essential for correcting errors and maintaining the integrity of the genome.
Is the POLD1 gene part of NHS genetic testing panels?
Yes, POLD1 is included in several NHS England PanelApp panels, such as those related to adult solid tumours cancer susceptibility and inherited polyposis. This indicates its recognised clinical significance for genetic testing within the UK.