The Fanconi anaemia (FANC)–BRCA1 pathway is required for DNA repair in response to damage caused by DNA crosslinking agents, such as cisplatin. Patients with ovarian cancer are given cisplatin as part of their standard therapy, but they often become resistant to this drug. The molecular mechanisms involved in cisplatin sensitivity and acquired resistance are unknown, so Taniguchi et al. investigated the role of the FANC–BRCA1 pathway in this process. The authors report in Nature Medicine that resistance of ovarian cancer cell lines to cisplatin depends on the methylation status of one of the key FANC genes, FANCF .

Five of the FANC proteins (A, C, E, F and G) are subunits of a nuclear complex that is required for mono-ubiquitylation of the FANCD2 protein, which interacts with BRCA1 to initiate repair. Two ovarian cancer cell lines that are hypersensitive to cisplatin do not express the mono-ubiquitylated form of FANCD2, but when the authors overexpressed FANCF — but not other FANC proteins — ubiquitylation of FANCD2, and its functionality, was restored. Consequently, the corrected cells were more resistant to cisplatin than the original cell line.

FANCF was not mutated in the cisplatin-sensitive cells but the gene contains a CpG island, which might inactivate it when methylated. The authors treated these cells with a demethylating agent — 5-aza-2′-deoxycytidine — which increased FANCF mRNA and protein expression and partially restored FANCD2 mono-ubiquitylation. Methylation-specific polymerase chain reaction confirmed that FANCF is methylated in the cisplatin-sensitive cell lines, but not in normal ovarian cells.

So, FANCF methylation can regulate cisplatin sensitivity, but does demethylation correlate with resistance? A cisplatin-resistant derivative of a cisplatin-sensitive ovarian cancer cell line expressed low levels of FANCF. Experimental overexpression of FANCF did not greatly increase the resistance of these cells, but sequencing of the CpG island showed that FANCF was demethylated in the resistant cells.

The authors suggest that FANCF is methylated and thereby inactivated early in ovarian cancer progression, and exposure to cisplatin at this stage leads to cell kill. However, in some tumour cells, FANCF then becomes demethylated, resulting in outgrowth of resistant cells. In the future, development of a targeted inhibitor of ubiquitylation of FANCD2 could bypass the influence of FANCF and be used to resensitize tumours in patients who have become resistant to cisplatin.