Further support for a G-quadruplex-dependent recombination mechanism comes from Cahoon et al. who identified a cis-acting

quadruplex motif near the variable pilin genes of the human pathogen Neisseria gonorrhoeae that controls recombination of the antigenically locus and avoid immune detection [ 35]. Disruption of the element either by mutagenesis or by targeting with a G-quadruplex ligand prevented selleck chemicals llc recombination and pilin antigenic variation. The Neisseria g. RecQ helicase is required to process nicks produced by the quadruplex forming sequence. An example of another apparently G-quadruplex related genetic disease has emerged from studies on ATRX, an X-linked gene of the SWI/SNF family, in which mutations lead to a rare form of syndromal mental retardation α-thalassaemia, caused by a downregulation of α-globin

expression [ 36]. Gibbons et al. showed that ATRX binds to G-rich tandem repeat sequences in both telomeres and euchromatin. Chip-Seq experiments on human and mouse confirmed the preference for ATRX to bind to G-quadruplex encoding DNA Alectinib mouse [ 37•] since 50% of ATRX binding sites overlapped with putative quadruplex sequences. Consistent with the binding of quadruplex structures, recombinant ATRX was shown to bind G-quadruplex DNA in vitro with high affinity. The genes associated with the ATRX-binding repeats show deregulated expression when ATRX is mutated. Specific attention was given to the variable tandem repeat within the cluster of alpha-like globin genes, and the authors demonstrated that a larger repeat led to a greater degree of down-regulation. Due to its important role in incorporating the histone variant H3.3 into telomeric, ribosomal and pericentromeric DNA, the authors propose that ATRX might act by modifying the epigenetic state of the guanine-rich repeats containing genes. A recent hypothesis suggests that G-quadruplex DNA is involved in the regulation and the maintenance of epigenetic regulation of gene expression. Studies on the Y family translesion polymerase REV1 in DT40

chicken cells Loperamide by Sale et al. showed that the presence of G-quadruplex DNA influences the preservation of histone marks in daughter chromosomes when the replication machinery is compromised [ 38]. The authors propose a model in which the failure to maintain processive DNA replication at G-quadruplex DNA in REV1-defficient cells leads to an uncoupling of DNA synthesis from histone recycling, resulting in localized loss of chromatin marks. Insertion of a G-quadruplex sequence in a silent locus, ρ-Globin, leads to expression derepression in REV1-defficient cells. A similar process caused deactivation of transcriptionally active genes and a microarray analysis of REV-1 deficient DT40 cells showed genome-wide reprogramming of gene transcription [ 39•].