DNA-protein crosslinks (DPCs) are formed when proteins are covalently and irreversibly bound to DNA. DPCs are highly genotoxic as their bulkiness obstruct nearly all chromatin-based processes. They can cause neurodegeneration, immunodeficiencies, and carcinogenesis. DPCs occur frequently in cells and can stem from both endogenous factors such as cellular aldehydes and exogenous factors such as environmental carcinogens and chemical agents. Notably, camptothecin derivatives, etoposide, and doxorubicin, which specifically induce topoisomerase DPCs and hence are known as topoisomerase poisons, are widely used as cancer chemotherapeutics. Cells employ a variety of mechanisms to repair DPCs. Proteolysis of the protein moiety of the DPC by the ubiquitin-proteasome system or other DPC-targeting proteases is a general strategy to debulk the DPC. Tyrosyl-DNA phosphodiesterases (TDPs) specifically hydrolyze the covalent bond between topoisomerases and DNA whereas the MRE11-RAD50-NBS1 (MRN) nuclease complex excises the DNA fragment of the DPC.
Any proteins located in the vicinity of DNA can result in non-specific DPCs, which can be induced by agents including reactive compounds like aldehydes. These are defined as non-enzymatic DPCs. Non-enzymatic DPCs can be degraded by proteases such as SPRTN and ACRC/GCNA during replication, but complete removal of the DPCs requires either cleavage of the covalent bond between the DNA and the protein or excision of the DNA fragment affected by the DPC using specific nucleases. Although it is well-established that TDPs and MRN can repair topoisomerase DPC through the aforementioned nucleolytic mechanisms, such nucleases for non-enzymatic DPCs have not yet been identified.
It remains obscure how enzymatic DPCs (such as PARP1, Polβ, DNMT1, MGMT-DPCs, HMCES) other than topoisomerase DPCs are repaired. Aditionally, it remains largely unknown whether TDPs, MRN, and potentially other nucleases can act on topoisomerase DPCs and other DPCs with or without the need for proteolysis.
DPC repair pathways are tightly regulated by post-translational modifications (PTMs) such as ubiquitylation, SUMOylation, poly-ADP-ribosylation, and phosphorylation, but it remains largely unknown if there is crosstalk among these PTMs and, if so, if the crosstalk(s) plays a role in DPC repair.
Determinants of the DPC repair pathway choices remain unknown, which have been hypothesized to involve cell cycle, DNA transactions, and PTMs.
In addition to the proteolytic and nucleolytic pathways, pathways such as the nucleotide excision pathway and the Fanconi anemia pathway have been implicated in DPC repair, but the detailed mechanisms remain unknown.
In this Research Topic, we aim to address the above-mentioned questions. This collection welcomes Original Research, Reviews, and other article types focusing on, but not limited to, the following themes:
• Causes and molecular mechanisms of DPC formation (chemical vs. enzymatic)
• General mechanisms for the repair of non-enzymatic DPCs.
• General mechanisms for the repair of enzymatic DPCs such as PARP1-, DNMT1, MGMT, and Polβ-DPCs in different settings.
• TDPs, MRN, and other nucleases for DPC repair.
• PTMS such as ubiquitylation, SUMOylation, and polyADP-ribosylation and their interplay in DPC repair.
• The determinant of DPC repair pathway choices.
• Canonical DNA repair pathways (BER, NER, MMR, Fanconi anemia, homologous recombination, and NHEJ) in DPC repair.
DNA-protein crosslinks (DPCs) are formed when proteins are covalently and irreversibly bound to DNA. DPCs are highly genotoxic as their bulkiness obstruct nearly all chromatin-based processes. They can cause neurodegeneration, immunodeficiencies, and carcinogenesis. DPCs occur frequently in cells and can stem from both endogenous factors such as cellular aldehydes and exogenous factors such as environmental carcinogens and chemical agents. Notably, camptothecin derivatives, etoposide, and doxorubicin, which specifically induce topoisomerase DPCs and hence are known as topoisomerase poisons, are widely used as cancer chemotherapeutics. Cells employ a variety of mechanisms to repair DPCs. Proteolysis of the protein moiety of the DPC by the ubiquitin-proteasome system or other DPC-targeting proteases is a general strategy to debulk the DPC. Tyrosyl-DNA phosphodiesterases (TDPs) specifically hydrolyze the covalent bond between topoisomerases and DNA whereas the MRE11-RAD50-NBS1 (MRN) nuclease complex excises the DNA fragment of the DPC.
Any proteins located in the vicinity of DNA can result in non-specific DPCs, which can be induced by agents including reactive compounds like aldehydes. These are defined as non-enzymatic DPCs. Non-enzymatic DPCs can be degraded by proteases such as SPRTN and ACRC/GCNA during replication, but complete removal of the DPCs requires either cleavage of the covalent bond between the DNA and the protein or excision of the DNA fragment affected by the DPC using specific nucleases. Although it is well-established that TDPs and MRN can repair topoisomerase DPC through the aforementioned nucleolytic mechanisms, such nucleases for non-enzymatic DPCs have not yet been identified.
It remains obscure how enzymatic DPCs (such as PARP1, Polβ, DNMT1, MGMT-DPCs, HMCES) other than topoisomerase DPCs are repaired. Aditionally, it remains largely unknown whether TDPs, MRN, and potentially other nucleases can act on topoisomerase DPCs and other DPCs with or without the need for proteolysis.
DPC repair pathways are tightly regulated by post-translational modifications (PTMs) such as ubiquitylation, SUMOylation, poly-ADP-ribosylation, and phosphorylation, but it remains largely unknown if there is crosstalk among these PTMs and, if so, if the crosstalk(s) plays a role in DPC repair.
Determinants of the DPC repair pathway choices remain unknown, which have been hypothesized to involve cell cycle, DNA transactions, and PTMs.
In addition to the proteolytic and nucleolytic pathways, pathways such as the nucleotide excision pathway and the Fanconi anemia pathway have been implicated in DPC repair, but the detailed mechanisms remain unknown.
In this Research Topic, we aim to address the above-mentioned questions. This collection welcomes Original Research, Reviews, and other article types focusing on, but not limited to, the following themes:
• Causes and molecular mechanisms of DPC formation (chemical vs. enzymatic)
• General mechanisms for the repair of non-enzymatic DPCs.
• General mechanisms for the repair of enzymatic DPCs such as PARP1-, DNMT1, MGMT, and Polβ-DPCs in different settings.
• TDPs, MRN, and other nucleases for DPC repair.
• PTMS such as ubiquitylation, SUMOylation, and polyADP-ribosylation and their interplay in DPC repair.
• The determinant of DPC repair pathway choices.
• Canonical DNA repair pathways (BER, NER, MMR, Fanconi anemia, homologous recombination, and NHEJ) in DPC repair.