FUTURE PERSPECTIVES
DNA GLYCOSYLASE FUNCTIONS BEYOND DNA REPAIR The functions of DNA glycosylases do not seem to be limited by canonical DNA
repair. Epigenetics is traditionally viewed upon as heritable changes in gene function, unexplainable by changes in DNA sequence (Russo et al., 1996). This restrictive definition excludes involvement of epigenetic phenomena in the functional state of for example the non-dividing neurons (Hong et al., 2005), and a more unifying definition is proposed by Bird: “The structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states” (Bird, 2007). This definition embodies the three major levels of epigenetic changes; modifications of DNA, modifications of histones, and remodeling of nucleosomes (Graff et al., 2011).
Accumulating evidence supports the involvement of BER in regulation of epigenetic states. For example, TDG complexes with activating histone modifiers to protect unmethylated gene promoter sequences from aberrant DNA hypermethylation, maintaining active chromatin states throughout cell differentiation (Cortazar et al.,
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52
2011). Patterns of DNA methylation play a crucial role in epigenetic transcriptional regulation during development and in disease. DNA methyltransferases (DNMTs) methylate cytosine at the C5 position to establish 5meC (Rottach et al., 2009). 5meC has long been the only known enzymatic modification to bases in mammalian genomic DNA, but recently, 5-hydroxymethylcytosine (5hmC) was rediscovered as a stable modification in the DNA of cerebellar Purkinje and granule cells (Kriaucionis et al., 2009). This finding suggested a role for 5hmC in epigenetic control of neuronal function. 5hmC is an intermediate in DNA demethylation (Tahiliani et al., 2009).
5meC is converted to 5hmC and further oxidized to 5-carboxylcytosine (5caC) by the ten eleven translocation (TET) family of dioxygenases (Guo et al., 2011; He et al., 2011). None of the mammalian DNA glycosylases possess activity for 5hmC, but TDG is also shown to specifically recognize and excise 5caC (He et al., 2011).
Further evidence also suggests BER as a player in active demethylation of DNA (Guo et al., 2011; Hajkova et al., 2010; Rai et al., 2008).
The purified human core catalytic domain of NEIL3 shows no detectable activity on single- or double stranded DNA oligos containing 5meC, 5hmC, or 5caC (personal communication, Erik S. Vik). Paper II and Paper III show a very specific loss of DNA repair activity on hydantoins in mouse Neil3-deficient NSPCs, but we know little of the physiological levels and significance of these lesions. It is shown that oxidized guanine at CpG sequences disrupts the methylation of DNA by DNMTs (Maltseva et al., 2009; Valinluck et al., 2004; Weitzman et al., 1994), and in sum, there is an emerging pattern involving oxidative DNA modifications and BER in control of epigenetic states to regulate proliferation and differentiation.
Epigenetic adaptation of promoter regions for transcriptional repression or activation may also be achieved by modification of histone residues. These mechanisms are involved in the genesis, differentiation, and plasticity of neurons (Graff et al., 2011). For example, histone acetylation on lysine residues is regulated by histone acetyltransferases and histone deacetylases (HDACs), unequivocally involved in hippocampus-dependent learning and memory (Alarcon et al., 2004; Graff et al., 2012; Guan et al., 2009; Levenson et al., 2004; Wood et al., 2005). Suggesting involvement of oxidative DNA damage repair in histone acetylation, inhibition of HDACs in rat neural stem cells seemingly increases the formation of 8-oxoG and enhances neuronal differentiation (Reis et al., 2012). As previously discussed, knockdown of Neil3 in these cells decreases the neuronal differentiation potential. To
further suggest involvement of BER in epigenetic adaptation of histones, the DNA glycosylase MutYH interacts with HDAC Hst4 in the fission yeast Schizosaccharomyces pombe (Chang et al., 2011). The aged brain seems to accumulate epigenetic silencing modifications, reducing the plasticity because of increased chromatin condensation (Graff et al., 2011). This could be a consequence of DNA damage accrual. We hypothesize that DNA damage recognition by Neil3 is involved in control of epigenetic states to regulate age-dependent neural plasticity.
Research efforts for cerebrovascular disease therapy have largely centered on the modulation of molecular and cellular cascades following ischemic injury.
Epigenetic approaches are emerging (Qureshi et al., 2010; Qureshi et al., 2011), including the inhibition of DNMTs (Endres et al., 2000; Endres et al., 2001) and HDACs to decrease the infarct volume and improve behavioral outcome (Faraco et al., 2006; Kim et al., 2007; Ren et al., 2004). HDAC inhibition also stimulates neurogenesis following ischemic injury (Kim et al., 2009). Unraveling the possible role of DNA glycosylases as modulators of epigenetic reprogramming in response to oxidative stress in neurodegenerative disease and cerebral ischemia may provide future therapeutic strategies to rescue and restore neurological function.
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