Impact of G-Quadruplexes on the Regulation of Genome Integrity, DNA Damage and Repair

Abstract

DNA G-quadruplexes (G4s) are known to be an integral part of the complex regulatory systems in both normal and pathological cells. At the same time, the ability of G4s to impede DNA replication plays a critical role in genome integrity. This review summarizes the results of recent studies of G4-mediated genomic and epigenomic instability, together with associated DNA damage and repair processes. Although the underlying mechanisms remain to be elucidated, it is known that, among the proteins that recognize G4 structures, many are linked to DNA repair. We analyzed the possible role of G4s in promoting double-strand DNA breaks, one of the most deleterious DNA lesions, and their repair via error-prone mechanisms. The patterns of G4 damage, with a focus on the introduction of oxidative guanine lesions, as well as their removal from G4 structures by canonical repair pathways, were also discussed together with the effects of G4s on the repair machinery. According to recent findings, there must be a delicate balance between G4-induced genome instability and G4-promoted repair processes. A broad overview of the factors that modulate the stability of G4 structures in vitro and in vivo is also provided here.

Impact of G-Quadruplex Structures on Methylation of Model Substrates by DNA Methyltransferase Dnmt3a

“…CD spectra of 19G4 were examined in buffer A containing 100 mM KCl; this K + concentration close to that in human cells (~150 mM KCl) was used in our G4-protein binding experiments and MTase-mediated methylation analysis. The CD spectrum of 19G4 recorded at room temperature revealed a typical parallel G4 fold with a positive peak at 265 nm and a negative one around 240 nm ( Figure 3 A) [ 30 ]. Using CD data recorded at different temperatures, we obtained the 19G4 melting curve ( Supplementary Figure S1 , inset), but due to the high thermal stability of quadruplex structure in the presence of 100 mM KCl, an accurate assessment of the 19G4 melting temperature (T m ) was not possible.…”

G-Quadruplex Formed by the Promoter Region of the hTERT Gene: Structure-Driven Effects on DNA Mismatch Repair Functions

“…The interplay between G4 structures and DNA repair machinery, the activity of which is coupled to genomic stability, has become the subject of intense research [ 23 ]. Here, we studied the functional responses of the DNA mismatch repair systems of two bacterial species to the tandem G4 structure formed by the noncoding strand of the hTERT promoter and its altered variants bearing point G>A substitutions (at positions 228, 250, 242/243, which are clustered in the middle of G4 motif) associated with cancer-causing driver mutations.…”

“…Indeed, G4s were shown to have diverse effects on the functioning of the major DNA repair systems: base excision repair (BER) and nucleotide excision repair (NER). While these noncanonical DNA forms stimulate the NER-mediated repair of UV-induced lesions such as pyrimidine dimers, they demonstrate opposite effects on the BER machinery by suppressing the removal of oxidative base lesions from G4 motifs [ 23 , 24 ]. Some of these data were obtained for oncogene promoters such as VEGF and c-Myc , which form only one intramolecular G4.…”

“…MutL then activates downstream repair, which involves a single-stranded break (nick) in the newly replicated strand, either by the MutH endonuclease in the methyl-directed MMR in E. coli, or by MutL itself in the methyl-independent MMR used by eukaryotes and most bacteria ( Figure 2 ). Escherichia coli MutS (ecMutS), Rhodobacter sphaeroides MutS and human MutSα were reported to bind to various single G4 DNA with an affinity greater than that for the G/T mismatch, but such preferential binding does not correlate with DNA mismatch repair activity; moreover, the modes of MutS binding to a G4 and to a mismatched base pair appear to be different [ 23 , 25 , 26 , 27 ]. We recently showed that MutL from E. coli (ecMutL) binds to a single parallel G4 formed by the d(GGGT) 4 sequence with a higher affinity than to double-stranded DNA.…”

Effects of G-Quadruplex-Binding Plant Secondary Metabolites on c-MYC Expression

“…In the cellular environments, the formation of the G4 structures in promoter regions occurs in competition with the DNA double helix and is regulated by various oppositely directed factors: chromatin opening, negative DNA supercoiling, different transcription enhancers and inhibitors, G4-stabilizing and destabilizing cellular proteins, exclusion of the C-rich strand from the B-DNA–G4 equilibrium due to the formation of a stable i-motif or co-transcriptional R-loop [ 55 ]. We hypothesize that the selective ligand binding to G4s may represent an additional factor contributing to G4 sequestration and prolongation of their lifetime in complex cellular environments.…”