title: DNA methyltransferase I is a mediator of doxorubicin-induced genotoxicity in human cancer cells.
abstract: Doxorubicin can induce the formation of extra-nuclear bodies during mitosis termed micronuclei but the underlying causes remain unknown. Here, we show that sub-lethal exposure to doxorubicin-induced micronuclei formation in human cancer cells but not in non-tumorigenic cells. Occurrence of micronuclei coincided with stability of DNMT1 upon doxorubicin assault, and DNMT1 was localized to the micronuclei structures. Furthermore, 5-aza-2'-deoxycytidine-mediated DNMT1 depletion or siDNMT1 knock-down attenuated the frequency of doxorubicin-induced micronucleated cells. Human DNMT1(-/-) cells displayed significantly fewer micronuclei compared to DNMT1(+/+) cells when challenged with doxorubicin, providing additional evidence for the involvement of DNMT1 in mediating such chromosomal aberrations. Collectively, our results demonstrate a role for DNMT1 in promoting DNA damage-induced genotoxicity in human cancer cells. DNMT1, recently identified as a candidate for doxorubicin-mediated cytotoxicity, is over-expressed in various cancer cell types. We propose that DNMT1 levels in tumor cells may determine the effectiveness of doxorubicin in chemotherapy.
authors.affiliation: Division of Cancer and Developmental Cell Biology, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore. tanhh@imcb.a-star.edu.sg
authors.forename: Hwee Hong
authors.initials: HH
authors.lastname: Tan
authors.forename: Alan George
authors.initials: AG
authors.lastname: Porter
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics*; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D006801:Humans; D015162:Micronucleus Tests; D009369:Neoplasms / Q000201:enzymology*
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human