POLA1 and Associated Diseases
Creative Biolabs is an innovative biotechnology company focused on the research of gene therapy. We are committed to the development of gene therapy, contributing rich experience and advanced analytical techniques for comprehensive solutions. We are always willing to share relevant information in this field with you. Here we give a brief introduction to the DNA polymerase alpha 1, catalytic Subunit (POLA1) gene.
Overview of POLA1
This gene is a protein-coding gene that encodes a protein that acts as the catalytic subunit of DNA polymerase, together with a regulatory subunit and two primase subunits, to form the DNA polymerase α complex. The catalytic subunit is closely linked to the initiation of DNA replication. In addition to its crucial role in DNA replication, POLA1 is also involved in the activation of type I interferons. Furthermore, POLA1 has multiple functions, such as exonuclease activity and DNA binding activity. It is worth noting that POLA1 is a key regulator in various pathways, such as purine metabolism, pyrimidine metabolism, and other metabolic pathways.
Diseases Associated with POLA1
- Colorectal cancer (CRC)
Data have shown that POLA1 levels are elevated in CRC cells and tissues compared with their normal counterparts. Furthermore, POLA1 expression levels were significantly higher in colon adenocarcinoma compared with other cancers, such as kidney, bladder, liver, and ovarian cancers. Therefore, elevated POLA1 expression is regarded as a relevant molecular feature and a potential therapeutic target in CRC.
- X-linked reticulate pigmentary disorder (XLPDR)
POLA1 mutations are strongly associated with various clinical manifestations, including type I interferon activation and immunodeficiency. XLPDR is a result of recurrent intronic mutations in POLA1. This is a rare syndrome characterized by sterile multiorgan inflammation, such as recurrent pneumonia and corneal inflammation, in addition to premature skin hyperpigmentation. Mutations elsewhere in the gene can cause various developmental changes and immune dysregulation.
Fig.1 Model depicting the effect of the XLPDR mutation on POLA1 mRNA splicing. (Starokadomskyy, 2021)
- Van Esch-O’driscoll syndrome (VEODS)
Many patients with classified mutations in coding and splice sites or POLA1 exhibited phenotypes distinct from XLPDR. The common features of these patients are short stature, severe intrauterine growth retardation, and varying degrees of growth delay. In addition, some patients also present with signs of hypogonadism. These new cases are all classified as VEODS syndrome.
Potential Molecular Mechanism of XLPDR
Mutations involving XLDPR create a new splice-donor site in intron 13, which results in partial missplicing of the POLA1 pre-mRNA, introducing a new exon 13a into the specific POLA1 transcript. It is noteworthy that the expression level of the misspliced transcript containing exon 13a was very low, which may be closely related to the inherent instability of this transcript. Despite the introduction of a frameshift mutation in abnormal exon 13a, expression of the truncated protein in XLPDR-derived cells has not been demonstrated so far.
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Reference
- Starokadomskyy, P.; et al. Immune dysfunction in mendelian disorders of POLA1 deficiency. Journal of Clinical Immunology. 2021, 41(2): 285-293.
