BACKGROUND: Glioblastoma multiforme (WHO grade IV) is a highly lethal brain tumor. Its malignancy is in part due to cell populations refractory to radiotherapy and chemotherapy, which in some patients display stem properties (glioma stem cells-GSC). We and others have recently shown that a major mechanism of resistance of GSC to therapies resides in their slow proliferation that in turn is linked to constitutive activation of the DNA damage response. FancD2, a central player of the Fanconi anemia pathway, is induced when replication forks stall at DNA damage sites. METHODS: We have analyzed the kinetics of FancD2 induction in two glioma cell lines with pronounced (Borru) and poor (DR177) stem phenotypes, by fluorescence analysis of nuclear foci. RESULTS: FancD2 activation was significantly delayed in Borru, consistent with the slow replication fork progression in these cells. On the contrary, no significant difference between Borru and DR177 was observed for pH2AX nuclear foci formation that hallmarks a number of DNA structure variations including double-strand breaks. CONCLUSION: GSC display reduced FancD2 activation following radiation damage, most probably due to their elongated cell cycle.
BACKGROUND:Glioblastoma multiforme (WHO grade IV) is a highly lethal brain tumor. Its malignancy is in part due to cell populations refractory to radiotherapy and chemotherapy, which in some patients display stem properties (glioma stem cells-GSC). We and others have recently shown that a major mechanism of resistance of GSC to therapies resides in their slow proliferation that in turn is linked to constitutive activation of the DNA damage response. FancD2, a central player of the Fanconi anemia pathway, is induced when replication forks stall at DNA damage sites. METHODS: We have analyzed the kinetics of FancD2 induction in two glioma cell lines with pronounced (Borru) and poor (DR177) stem phenotypes, by fluorescence analysis of nuclear foci. RESULTS:FancD2 activation was significantly delayed in Borru, consistent with the slow replication fork progression in these cells. On the contrary, no significant difference between Borru and DR177 was observed for pH2AX nuclear foci formation that hallmarks a number of DNA structure variations including double-strand breaks. CONCLUSION: GSC display reduced FancD2 activation following radiation damage, most probably due to their elongated cell cycle.
Authors: Toshiyasu Taniguchi; Irene Garcia-Higuera; Paul R Andreassen; Richard C Gregory; Markus Grompe; Alan D D'Andrea Journal: Blood Date: 2002-10-01 Impact factor: 22.113
Authors: Ben C Shirley; Eliseos J Mucaki; Tyson Whitehead; Paul I Costea; Pelin Akan; Peter K Rogan Journal: Genomics Proteomics Bioinformatics Date: 2013-03-14 Impact factor: 7.691