- Type I topoisomerases are enzymes responsible for regulating DNA topology by relaxing supercoiled DNA. Unlike type II topoisomerases, which cleave both DNA strands, type I topoisomerases function by introducing transient single-strand breaks, allowing DNA to unwind and relieve torsional stress.
- These enzymes are essential for DNA replication, transcription, and chromatin organization, ensuring smooth cellular processes and genomic stability.
- Type I topoisomerases are monomeric enzymes that operate without ATP, utilizing the energy stored in supercoiled DNA to carry out strand relaxation. They are classified into two major subfamilies:
- Type IA Topoisomerases – Bind single-stranded DNA and work via a strand-passage mechanism. Found in bacteria and some eukaryotes, examples include bacterial topoisomerase I (topA gene product).
- Type IB Topoisomerases – Bind double-stranded DNA and work via a controlled rotation mechanism. These enzymes are widely present in eukaryotic cells, including human topoisomerase I.
- The enzyme consists of a DNA-binding domain and a catalytic core that facilitates strand cleavage, passage, and religation, ensuring minimal DNA damage while regulating supercoiling levels.
- Type I topoisomerases solve topological challenges in DNA by introducing single-strand breaks and allowing controlled rotation or strand passage. Their primary functions include:
- Supercoiling relaxation – Prevents excessive DNA winding that occurs during replication and transcription.
- Gene expression regulation – Ensures smooth progression of RNA polymerase along the DNA template.
- Chromatin organization – Plays a role in nucleosome positioning and DNA accessibility.
- Their mechanism involves a transient nick in one DNA strand, followed by controlled rotation or strand passage to relieve tension, after which the enzyme re-ligates the strand, ensuring DNA integrity.
- Type I topoisomerases serve as targets for anticancer drugs, particularly topoisomerase I inhibitors such as camptothecin and its derivatives (irinotecan, topotecan). These drugs stabilize the topoisomerase-DNA complex after cleavage, preventing DNA re-ligation and leading to lethal double-strand breaks when replication occurs.
- While bacterial type I topoisomerases are not primary antibiotic targets like DNA gyrase or topoisomerase IV, their function remains essential for bacterial survival, making them potential candidates for future antimicrobial research.
