Aldehyde-induced DNA-protein crosslinks- DNA damage, repair and mutagenesis

Abstract

Aldehyde exposure has been shown to lead to the formation of DNA damage comprising of DNA-protein crosslinks (DPCs), base adducts and interstrand or intrastrand crosslinks. DPCs have recently drawn more attention because of recent advances in detection and quantification of these adducts. DPCs are highly deleterious to genome stability and have been shown to block replication forks, leading to wide-spread mutagenesis. Cellular mechanisms to prevent DPC-induced damage include excision repair pathways, homologous recombination, and specialized proteases involved in cleaving the covalently bound proteins from DNA. These pathways were first discovered in formaldehyde-treated cells, however, since then, various other aldehydes have been shown to induce formation of DPCs in cells. Defects in DPC repair or aldehyde clearance mechanisms lead to various diseases including Ruijs-Aalfs syndrome and AMeD syndrome in humans. Here, we discuss recent developments in understanding how aldehydes form DPCs, how they are repaired, and the consequences of defects in these repair pathways.

Keywords: DNA damage; DNA protein crosslink; DNA repair; aldehydes; genome instability.

Figure 1

Formation of formaldehyde-induced (A) lysine-deoxyguanosine and (B) cysteine-deoxyguanosine crosslinks. Formation of a lysine-deoxyguanosine crosslink requires the formation of a methylol followed by dehydration to form a reactive Schiff base. The Lys-CH₂-dG crosslink is the most common formaldehyde-induced crosslink. Formation of the cysteine-deoxyguanosine crosslink requires the formation of a S-hydroxymethyl adduct which can then directly react with deoxyguanosine. The Cys-CH₂-dG crosslink is the most stable formaldehyde-induced crosslink. R₁ and R₂ represent the attachment of lysine (A) or cysteine (B) to a larger polypeptide chain. R₃ represents the attachment of guanine to a deoxyribose group and DNA strand.

Figure 2

Aldehyde-induced DNA-protein crosslinks and their repair. Several biologically significant aldehydes can generate DPCs, and their structures can be seen at the top of the figure. DPC repair can be carried out by dedicated proteases like Wss1 (SPRTN), Ddi1, and the proteasome. DPCs may also be repaired by more classical pathways including nucleotide excision repair (NER) and homologous recombination (HR). Importantly, DPC repair most likely involves a combination of these pathways. For example, partial degradation of a DPC by the proteasome followed by NER to remove the remaining adduct. Yeast protein names are written with their human counterparts in parenthesis.