Regulation of DNA (Cytosine-5) Methyltransferase 1 in the cell cycle and its role(s) in doxorubicin-mediated micronuclei formation

Abstract

The expression of DNMT1 is critical in coordinating DNMT1 activity with biological processes and therefore must be tightly regulated in the cell cycle. Several studies have shown that DNMT1 expression level is inversely correlated with p21WAF1 protein, but the exact mechanism remained unresolved. Interestingly, I identified p21WAF1 as a novel upstream regulator of DNMT1 expression in mammalian cell lines. p300, which serves as a crucial transcription co-activator for DNMT1, emerged as an important mediator for the negative regulation of DNMT1 by p21WAF1. Aside from elucidating the mechanism involved in regulating DNMT1, the involvement of DNMT1 in DNA damage response was studied. Doxorubicin can induce the formation of extranuclear bodies during mitosis termed micronuclei, but the underlying causes remain unknown. Interestingly, my work provides strong evidence for the involvement of DNMT1 in promoting genomic instability in the form of micronuclei formation in human cancer cells upon sub-lethal exposure to doxorubicin.