Genetic or epigenetic inactivation of the pathway formed by the Fanconi Anemia (FA) and BRCA proteins occurs in several cancer types, including lung and breast cancer, rendering the affected tumors potentially hypersensitive to DNA crosslinking agents. However, the cytotoxicity of other commonly used cancer therapeutics in cells with FA/BRCA pathway defects remains to be defined. Building on earlier data that implicated BRCA1 and BRCA2 in the repair of DNA damage caused by the topoisomerase II poison etoposide, we studied the role of FANCD2 in mediating resistance to several topoisomerase II poisons. We establish that the loss of FANCD2 increases cell death in response to etoposide. FANCD2 promotes homologous recombination repair (HRR) and prevents DNA double-strand break formation and chromosomal aberrations in etoposide-treated cells. Strikingly, this function of FANCD2 is independent of FANCD2 foci formation and of FANCA, which is a member of the FA core complex upstream of FANCD2 mono-ubiquitination. Thus, FANCD2 appears to promote HRR in a mono-ubiquitination-independent manner in conjunction with BRCA1/2. These data add to an emerging body of evidence indicating that the FA pathway is not linear and that several protein subcomplexes with different functions exist. Our findings are potentially relevant for predicting the sensitivity of lung and breast cancers to etoposide and doxorubicin, respectively.
Genetic or epigenetic inactivation of the pathway formed by the Fanconi Anemia (FA) and BRCA proteins occurs in several cancer types, including lung and breast cancer, rendering the affected tumors potentially hypersensitive to DNA crosslinking agents. However, the cytotoxicity of other commonly used cancer therapeutics in cells with FA/BRCA pathway defects remains to be defined. Building on earlier data that implicated BRCA1 and BRCA2 in the repair of DNA damage caused by the topoisomerase II poison etoposide, we studied the role of FANCD2 in mediating resistance to several topoisomerase II poisons. We establish that the loss of FANCD2 increases cell death in response to etoposide. FANCD2 promotes homologous recombination repair (HRR) and prevents DNA double-strand break formation and chromosomal aberrations in etoposide-treated cells. Strikingly, this function of FANCD2 is independent of FANCD2 foci formation and of FANCA, which is a member of the FA core complex upstream of FANCD2 mono-ubiquitination. Thus, FANCD2 appears to promote HRR in a mono-ubiquitination-independent manner in conjunction with BRCA1/2. These data add to an emerging body of evidence indicating that the FA pathway is not linear and that several protein subcomplexes with different functions exist. Our findings are potentially relevant for predicting the sensitivity of lung and breast cancers to etoposide and doxorubicin, respectively.