DNA and RNA polymerase incorporation sites

DNA and RNA polymerase incorporation sites represent the catalytic pockets within polymerase enzymes where nucleotide triphosphates are positioned and covalently linked to a nascent DNA or RNA primer strand [1]. These sites are fundamental to the processes of genomic replication, DNA repair, and gene transcription across all domains of life and in many viruses [2]. In a therapeutic context, these sites are the functional targets for nucleoside and nucleotide analogs, which are designed to compete with endogenous substrates [3]. Upon binding and subsequent incorporation into the growing chain, these analogs typically act as obligate or non-obligate chain terminators, effectively halting the synthesis of the nucleic acid polymer [1][4]. This mechanism is widely exploited in the treatment of viral infections, such as HIV, Hepatitis B and C, and COVID-19, as well as in oncology to inhibit the proliferation of malignant cells [3][5]. However, the therapeutic index of drugs targeting these sites depends heavily on their selectivity for viral or tumor-specific polymerases over essential host enzymes [6]. Off-target incorporation by human mitochondrial DNA polymerase gamma, for instance, can lead to significant clinical toxicities including organ failure and lactic acidosis [6][7].

Other names

Polymerase active siteNucleotide binding pocketNascent chain incorporation sitedNTP binding siteNucleoside analog incorporation site

Competitive inhibition of natural nucleotides followed by incorporation into the nascent nucleic acid strand, leading to chain termination or lethal mutagenesis.