DNA methylation/demethylation constitutes a major consequence in all biological processes involving transcription, differentiation, development, DNA repair, recombination, and chromosome organization. Our earlier studies established that demethylation of CpG rich sequence by human
DNA demethylase activity (5-methylcytosine-DNA glycosylase (5MeC-DNA glycosylase)) resembles "base excision DNA repair activity" and creates single-strand breaks on
DNA that is associated with
proliferating cell nuclear antigen (
PCNA). Here in this report, we have identified differential DNA demethylation targets (hemi-methylated vs. fully-methylated) in normal cell lines and cancerous cell lines, and a shortened G(0)/G(1) resting time in cancerous cell lines than the normal cell lines. We have identified that in normal HFL1 fibroblast cell line,
DNA demethylase activity targets hemi-methylated CpG specific sites on
DNA. This normal cell line
DNA demethylase activity associates with
PCNA immune complex that is inhibited by
CDKI proteins p21(waf1)/Gadd45alpha and Gadd45beta. While in cancerous LnCap and BT20 cell lines
DNA demethylase activity targets fully-methylated CpG specific sites on
DNA. This
cancer cell line
DNA demethylase activity is not associated with
PCNA immune complex and is not inhibited by
CDKI proteins p21(waf1)/Gadd45alpha and Gadd45beta. We have also identified that the fully-methylated CpG specific
DNA demethylase activity from cancerous cell lines to associate with
p300/CBP protein. These significant observations of variable targets of DNA demethylation and alternate partner
proteins for
DNA demethylase activity in cancerous cell lines are discussed in terms of double-strand DNA breaks versus single-strand DNA breaks and their role in the exit of G(1)/G(2) cell cycle stages. Also, the inability of
cell cycle regulatory proteins like
PCNA, p21(waf1), and Gadd45 to control
DNA demethylase activity in cancerous cell lines is discussed in terms of accelerated G(1)/G(2) cell cycle stage exit to facilitate unregulated cellular proliferation, loss of control of chromosomal organization, and the development of
oncogenesis in cancerous cell lines.