TDP1 Human

Tyrosyl-DNA Phosphodiesterase 1 is a member of the phospholipase D family and contains two PLD phosphodiesterase domains . The primary function of TDP1 is to catalyze the hydrolysis of the phosphodiester bond between the tyrosine residue of Type I topoisomerase and the 3-prime phosphate of DNA . This activity is essential for repairing DNA damage caused by topoisomerase I inhibitors, which are often used in cancer therapy .

The enzyme activity of TDP1 was first reported in 1996 by Howard Nash and colleagues . Three years later, the gene encoding this enzyme was identified, marking a significant milestone in understanding DNA repair mechanisms . The TDP1 gene is located on chromosome 14 in humans .

TDP1 is involved in the repair of single-strand and double-strand DNA breaks. It achieves this by removing glycolate from single-stranded DNA containing 3-prime phosphoglycolate, which suggests a role in repairing free-radical mediated DNA double-strand breaks . This enzyme is also known to interact with other proteins involved in DNA repair, enhancing its role in maintaining genomic stability .

Mutations in the TDP1 gene are associated with a rare neurodegenerative disorder known as spinocerebellar ataxia with axonal neuropathy (SCAN1) . This condition highlights the importance of TDP1 in neural function and DNA repair. Additionally, TDP1’s role in counteracting the effects of topoisomerase I inhibitors makes it a potential target for enhancing the efficacy of cancer treatments .

Recent research has focused on identifying inhibitors of TDP1 to improve the effectiveness of topoisomerase I inhibitors in cancer therapy . Small molecule microarray screenings have identified several compounds that bind to the TDP1 catalytic pocket, offering promising avenues for drug development .