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Nat Rev Mol Cell Biol. 2017 Sep;18(9):563-573. doi: 10.1038/nrm.2017.56. Epub 2017 Jun 28.

Mechanisms of DNA-protein crosslink repair.

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1
The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.

Abstract

Covalent DNA-protein crosslinks (DPCs, also known as protein adducts) of topoisomerases and other proteins with DNA are highly toxic DNA lesions. Of note, chemical agents that induce DPCs include widely used classes of chemotherapeutics. Their bulkiness blocks virtually every chromatin-based process and makes them intractable for repair by canonical repair pathways. Distinct DPC repair pathways employ unique points of attack and are crucial for the maintenance of genome stability. Tyrosyl-DNA phosphodiesterases (TDPs) directly hydrolyse the covalent linkage between protein and DNA. The MRE11-RAD50-NBS1 (MRN) nuclease complex targets the DNA component of DPCs, excising the fragment affected by the lesion, whereas proteases of the spartan (SPRTN)/weak suppressor of SMT3 protein 1 (Wss1) family target the protein component. Loss of these pathways renders cells sensitive to DPC-inducing chemotherapeutics, and DPC repair pathways are thus attractive targets for combination cancer therapy.

PMID:
28655905
DOI:
10.1038/nrm.2017.56
[Indexed for MEDLINE]

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