Formation and repair of DNA-protein crosslink damage

Abstract

DNA is constantly exposed to a wide array of genotoxic agents, generating a variety of forms of DNA damage. DNA-protein crosslinks (DPCs) – the covalent linkage of proteins with a DNA strand – are one of the most deleterious and understudied forms of DNA damage, posing as steric blockades to transcription and replication. If not properly repaired, these lesions can lead to mutations, genomic instability, and cell death. DPCs can be induced endogenously or through environmental carcinogens and chemotherapeutic agents. Endogenously, DPCs are commonly derived through reactions with aldehydes, as well as through trapping of various enzymatic intermediates onto the DNA. Proteolytic cleavage of the protein moiety of a DPC is a general strategy for removing the lesion. This can be accomplished through a DPC-specific protease and and/or proteasome-mediated degradation. Nucleotide excision repair and homologous recombination are each involved in repairing DPCs, with their respective roles likely dependent on the nature and size of the adduct. The Fanconi anemia pathway may also have a role in processing DPC repair intermediates. In this review, we discuss how these lesions are formed, strategies and mechanisms for their removal, and diseases associated with defective DPC repair.

The Aspartic Protease Ddi1 Contributes to DNA-Protein Crosslink Repair in Yeast

“…SPRTN, in contrast, possesses ubiquitin-binding motifs, binds PCNA, is cell-cycle regulated and activated by de-ubiquitination and ssDNA (Larsen et al, 2018;Mosbech et al, 2012;Stingele et al, 2016). In addition to the dedicated proteolytic mechanism, it was proposed previously and confirmed recently that the 26S proteasome is directly involved in DPC proteolysis (Klages-Mundt and Li, 2017;Larsen et al, 2018;Lin et al, 2008;Quievryn and Zhitkovich, 2000). In addition, the CMG helicase can bypass DPCs with the help of RTEL1 prior to proteolysis, however SPRTN and 26S proteasome activities remain the prerequisite for the full performance of a downstream repair pathway (Sparks et al, 2019).…”

“…The crosslinking agents include but are not limited to reactive aldehydes, ionizing radiation, UV light, or metal ions (Ide et al, 2018). Several spontaneous or druginduced abortive enzymatic reactions catalyzed by topoisomerases, PARP1, DNA Polb, DNMT1, etc, can also result in the formation of DPCs (Klages-Mundt and Li, 2017;Stingele et al, 2017). Canonical repair pathways, including homologous recombination (HR) and nucleotide excision repair (NER), are required for cell survival in the presence of DPCs (de Graaf et al, 2009;Nakano et al, 2009).…”

SUMO orchestrates multiple alternative DNA-protein crosslink repair pathways

“…DNA-protein complexes are typically dissociated in the order of seconds (Phair et al, 2004), while formation of an aberrant covalent bond abrogates this process. Persistent DNA-protein crosslinks (DPCs) are highly toxic if not resolved in a timely manner, as they cause genome instability and eventually promote cell death (Ide et al, 2018;Klages-Mundt and Li, 2017;Stingele et al, 2017).…”

Untitled

“…Protein carbonylation has been found to play a vital role in the pathogenesis of numerous diseases 4 . Reactive species can also modify DNA bases, induce interand intra-strand crosslinks, promote DNA-protein crosslinks, produce sugar moiety modifications and create strand break 5 . Accumulation of DNA damage induces mutagenesis that results in carcinogenesis 6 .…”