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• W1995204735 abstract "<h3>Background</h3> Gene amplification is a frequent manifestation of genomic instability that plays a role in tumour progression and development of drug resistance. It is manifested cytogenetically as extrachromosomal double minutes (DMs) or intrachromosomal homogeneously staining regions (HSRs). To better understand the molecular mechanism by which HSRs and DMs are formed and how they relate to the development of methotrexate (MTX) resistance, we used two model systems of MTX-resistant HT-29 colon cancer cell lines harbouring amplified <i>DHFR</i> primarily in (i) HSRs and (ii) DMs. <h3>Results</h3> In DM-containing cells, we found increased expression of non-homologous end joining (NHEJ) proteins. Depletion or inhibition of DNA-PKcs, a key NHEJ protein, caused decreased <i>DHFR</i> amplification, disappearance of DMs, increased formation of micronuclei or nuclear buds, which correlated with the elimination of <i>DHFR,</i> and increased sensitivity to MTX. These findings indicate for the first time that NHEJ plays a specific role in DM formation, and that increased MTX sensitivity of DM-containing cells depleted of DNA-PKcs results from <i>DHFR</i> elimination. Conversely, in HSR-containing cells, we found no significant change in the expression of NHEJ proteins. Depletion of DNA-PKcs had no effect on <i>DHFR</i> amplification and resulted in only a modest increase in sensitivity to MTX. Interestingly, both DM-containing and HSR-containing cells exhibited decreased proliferation upon DNA-PKcs depletion. <h3>Conclusions</h3> We demonstrate a novel specific role for NHEJ in the formation of DMs, but not HSRs, in MTX-resistant cells, and that NHEJ may be targeted for the treatment of MTX-resistant colon cancer." @default.
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• W1995204735 date "2014-12-23" @default.
• W1995204735 modified "2023-09-26" @default.
• W1995204735 title "Novel role for non-homologous end joining in the formation of double minutes in methotrexate-resistant colon cancer cells" @default.
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• W1995204735 doi "https://doi.org/10.1136/jmedgenet-2014-102703" @default.
• W1995204735 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4316941" @default.
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