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The intertwined nature of the DNA double helix creates topological barriers that need to be resolved during all types of DNA transactions, in all forms of life from plant to man.
DNA topoisomerases achieve this by breaking and sealing the double helix, allowing the DNA to become untangled or unwound. During their normal catalytic cycle DNA topoisomerases become covalently attached to the DNA 3’-end (Top1) or to the 5’-end (Top2) via a reversible covalent phosphotyrosyl bond.
The presence of nearby oxidative DNA breaks (red circles) or collision with elongating RNA polymerases (RNA POL) during transcription results in ‘trapping’ of topoisomerases on DNA, causing protein-linked DNA breaks (PDBs), which are potent blocks to transcription and cell viability.
PDBs are repaired by a nucleolytic cleavage of DNA releasing the stalled Top and a fragment of DNA. Since this process results in an inevitable loss of genetic material, it is inherently error-prone.
Alternatively, PDBs can be repaired by an error-free mechanism in which the covalent phosphotyrosyl bond linking DNA to the stalled Top is cleaved by specific enzymes, such as tyrosyl DNA phosphodiesterases (TDP1 and TDP2). Interestingly, defects in TDPs cause neurological disease in man (see Fig.2).
In addition to maintaining genetic integrity in post-mitotic non cycling cells, accumulation of PDBs in cycling cells has been widely exploited to treat cancer (e.g. topoisomerase poisons such as Irinotecan and Topotecan), and therefore small molecule inhibitors of TDPs are emerging as attractive strategies to improve cancer therapy.
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DNA REPAIR (2024): 103629-103629
Marwa Matboli,Mohmed Kamal Hassan,Mahmoud A Ali, Mohamed Tarek Mansour,Waheba Elsayed,Reham Atteya, Hebatallah Said Aly,Mahmoud El Meteini,Hesham Elghazaly,Sherif El-Khamisy,Sara H A Agwa
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