DNA methyltransferase I is a mediator of doxorubicin-induced genotoxicity in human cancer cells.
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.
Tan
Hwee Hong
HH
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
Porter
Alan George
AG
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*
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human