Covalent DNA–protein crosslinks (DPCs) are highly toxic DNA lesions that are induced by widely used classes of chemotherapeutics and also by various external and endogenous agents.
DPCs consist of three distinct components, which are harnessed by distinct repair mechanisms as a starting point for repair.
Tyrosyl-DNA phosphodiesterases directly hydrolyse the covalent bond between protein and DNA at DPCs.
Nuclease-dependent repair by the MRE11–RAD50–NBS1 (MRN) complex targets the DNA component of DPCs.
Proteolytic repair by the spartan (SPRTN)/weak suppressor of SMT3 protein 1 (Wss1) protease family degrades the protein component of DPCs.
Inhibition of DPC repair pathways offers novel therapeutic opportunities for anticancer combination therapies.
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.
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The authors apologize to those whose important findings could not be mentioned as primary literature and/or cited owing to space constraints. The authors thank S. Panier and G. Hewitt for comments and discussions. J.S. is supported by an EMBO Long-term Fellowship (ALTF 470–2015). S.J.B.'s laboratory is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC0010048), the UK Medical Research Council (FC0010048), and the Wellcome Trust (FC0010048); European Research Council (ERC) Advanced Investigator Grants (RecMitMei; TelMetab); and a Wellcome Trust Senior Investigator Grant.
The authors declare no competing financial interests.
- Abasic sites
Positions within DNA that lack a DNA base; also known as apurinic or apyrimidinic (AP) sites. They can occur spontaneously or through base excision by DNA glycosylases.
- Intrastrand and interstrand DNA crosslinks
Chemical crosslinking of DNA can occur between positions on the same DNA strand (intrastrand) or between opposing strands (interstrand).
- Poly(ADP-ribose) polymerase 1
(PARP1). A member of a family of enzymes that catalyse the formation of poly(ADP-ribose) chains, thereby regulating various cellular processes, most notably DNA repair.
Any molecule that inhibits an enzyme by mimicking a substrate.
- Homologous recombination
(HR). A process resulting in the exchange of identical or highly similar DNA sequences between two DNA molecules; it is involved in meiosis, DNA repair and DNA replication.
- DNA polymerase β
The DNA polymerase required for gap filling during base excision repair and DNA single-strand break repair.
A medical condition that is characterized by a lack of coordination of voluntary muscle movements; it is often caused by inherited or acquired cerebellum diseases (cerebellar ataxia).
The absence of neurological reflexes.
Small dilated blood vessels in the outer layer of the skin or in mucosae. Usually a benign condition, which can be associated with serious genetic or acquired diseases.
A neurological motor disorder that is caused by partial brain damage; affected individuals experience difficulty with motor planning to carry out motor tasks or movements.
A motor speech disorder characterized by poor articulation of phonemes. It is caused by injuries to the motor component of the motor–speech system of the brain.
A neurological condition in which affected individuals present with a smaller than normal head owing to defective brain development.
A medical condition that is characterized by underdevelopment of the jaw.
A protein complex that degrades unneeded or damaged proteins. Proteins are commonly marked for degradation by modification with polyubiquitin chains.
A post-translational modification, also known as polyADP-ribosylation, by which polymers of ADP-ribose are attached to substrate proteins by poly(ADP-ribose) polymerases (PARPs).
- X-ray repair cross-complementing protein 1
(XRCC1). A molecular scaffold protein that orchestrates the repair of DNA single-strand breaks by recruiting and stabilizing multiple other repair factors.
- Ataxia telangiectasia mutated
(ATM). A protein kinase best known for its function in signalling the presence of DNA double-strand breaks, thereby activating a highly sophisticated cellular response.
- DNA-dependent protein kinase
(DNA-PK). Heterotrimeric DNA-dependent kinase that comprises KU70, KU80 and the catalytic subunit DNA-PKcs; best known for its central function in non-homologous end joining repair of DNA double-strand breaks.
- Replication fork run-off
If a replication fork encounters a single-strand break, the replicative helicase runs off the template strand, resulting in the formation of a highly toxic single-ended DNA double-strand break.
- Non-homologous end joining
(NHEJ). The repair of DNA double-strand breaks by directly ligating two DNA ends, irrespective of DNA sequence.
A type II DNA topoisomerase that is required for the generation of DNA double-strand breaks during meiosis, which is crucial for genetic recombination.
- Synthetic lethality screen
A genetic screening method, which aims to reveal genes that when knocked out cause lethality in combination with a knockout of a gene of interest.
- DNA damage checkpoint
A cellular signalling mechanism that pauses the cell cycle in response to the presence of DNA damage, thereby providing enough time to ensure that repair can occur before the next cell division.
A diverse class of enzymes that are involved in various cellular processes. AAA-ATPases use energy obtained from ATP hydrolysis to generate mechanical forces through conformational changes.
- Hypomorphic mutations
Mutations that cause a partial loss of function; for example, by reduced gene expression or decreased protein stability. Hypomorphic mutations mostly display less severe phenotypes than a complete gene loss.
- Hepatocellular carcinomas
The most common type of liver cancer; often caused by hepatitis virus (B or C) and substances such as aflatoxin and ethanol.
- Translesion synthesis polymerases
DNA polymerases with the ability to synthesize past DNA lesions due to a flexible active site; they often display low fidelity and thus tend to incorporate mutations.
- Nucleotide excision repair
(NER). A DNA repair pathway that repairs primarily bulky adducts, such as those induced by ultraviolet (UV) light. Repair is achieved by excision of a short stretch of nucleotides that contains the DNA lesion.
- Template switch
A recombination process that allows the replication of damaged DNA strands by using the newly replicated sister strand as a template for DNA synthesis.
- Mismatch repair
A conserved DNA repair pathway that detects and repairs base–base mismatches and insertion–deletion mispairs, which can be generated by mistakes during replication.
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Stingele, J., Bellelli, R. & Boulton, S. Mechanisms of DNA–protein crosslink repair. Nat Rev Mol Cell Biol 18, 563–573 (2017). https://doi.org/10.1038/nrm.2017.56
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