DNA MODIFICATIONS DRIVE DNA STRUCTURE AND FUNCTION

Since Watson and Crick proposed the model of the right-handed double helix, which was later called B-DNA, the field has come to appreciate that this particular conformational state is but one possible shape. In fact, when the crystal structure of DNA was revealed, the field was amazed to discover that DNA could also assume a zig-zag confirmation with a left-handed double helix, which was completely opposite to that proposed 25 years earlier (Wang et al., 1979). It is evident that this interesting conformational state of DNA, or Z-DNA as it became known, together with at least 20 other possible DNA states such as the G-quadruplex, which interacts with DNA helicases and other epigenetic regulators, have very important biological functions in the cell (Murat & Balasubramanian, 2014; Rich & Zhang, 2003). It is now known that the structural properties of DNA can influence its ability to recognize and interact with transcription factors and other protein partners that, in turn, drive gene expression as well as coordinating the organization and integrity of the genome (Parker et al., 2009; Rohs et al., 2009; Rohs, West, et al., 2009; H. Zhou et al., 2015; K.I. Zhou et al., 2015; and reviewed in Harteis & Schneider, 2014).

Perhaps most important for this discussion, the structural reactivity and conformational state of DNA is profoundly influenced by base modifications. DNA methylation decreases the flexibility of DNA to interfere with the exaggerated bending of DNA required to form nucleosomes (Nathan & Crothers, 2002), resulting in a further shortening of the regions of linker DNA (Choy et al., 2010) that can alter the conformational space of a gene (Bettecken, Frenkel, & Trifonov, 2011). Specifically, the accumulation of the cytosine modification 5-formylcytosine (5fC) results in the formation of a DNA structure called F-DNA, which is characterized by helical underwinding (Raiber et al., 2015). This modification is thought to impact DNA supercoiling as well as the packaging of DNA into chromatin, both of which are related to transcription. Moreover, 5hmC inhibits the transition from B- to Z-DNA, whereas the oxidized derivatives 5fC and 5-carboxylcytosine seem to promote this process (Nickol, Behe, & Felsenfeld, 1982; Wang et al., 2014). Interestingly, Z-DNA occurs predominantly in a CpG dinucleotide context within repetitive elements across the genome (ie, CpG islands). Z-DNA is also found near promoter regions and, like F-DNA, stimulates gene transcription (Oh, Kim, Rich, 2002; Rich & Zhang, 2003). A hallmark feature of G-quadruplex DNA is that it tends to occur in hypomethylated regions, and it is associated with genome instability and DNA damage (De & Michor, 2011).

 
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