MYC is an all-singing, all-dancing oncogene. Not only does it induce cell proliferation, but there is evidence that it might also contribute to invasion, angiogenesis and genomic instability — all of which have implications for tumour formation. Dean Felsher and colleagues, reporting in the Proceedings for the National Academy of Sciences, have further investigated the role in genomic instability, and propose that MYC interferes with the repair of DNA double-strand breaks (DSBs).

Overexpression of MYC is known to lead to gene amplifications and fusions, which could be caused by defective DSB repair. To test this hypothesis, the authors generated normal human foreskin fibroblasts that contained a regulatable MYC gene. Overexpression of MYC was shown to increase the number of γ-H2AX foci — a marker of DSB repair. But does MYC cause the DSBs themselves or prevent their repair?

This was investigated by irradiating cells to introduce DSBs either in the presence or absence of MYC. Following this treatment, the number of γ-H2AX foci increased, regardless of whether or not MYC was expressed. However, in cells that did not express MYC, the γ-H2AX foci disappeared with an hour of treatment; in cells expressing MYC, the foci remained for up to 3 hours, indicating that MYC does not affect the generation of DSBs, but does interfere with their repair.

Felsher and colleagues next looked at the effect of MYC expression on the repair of a single DSB. The DRAA8 cell line has been engineered to contain the green fluorescent protein (GFP) gene, which is activated by a homologous recombination event following the introduction of a single DSB by the restriction enzyme I-Sce-I; repair can be monitored by expression of GFP. Transfection of I-Sce-I resulted in an increase in the number of GFP-positive cells, but expression of MYC reduced this back to background levels. A PCR-based assay confirmed that MYC could suppress DSB repair through non-homologous end joining and single-strand annealing, as well as through homologous recombination. The effect on DNA repair seems to be specific to DSBs though, as MYC expression has no effect on nucleotide excision repair of ultraviolet-light-induced lesions.

But can MYC expression result in genomic instability in normal cells by failing to repair DSBs that spontaneously occur? This was examined in a single cell cycle using synchronized normal human foreskin cells. Interestingly, MYC expression induced a high frequency of chromatid breaks (12%), deletions (3%) and translocations (3%), compared with only rare breaks and no deletions and translocations in cells that did not express MYC.

So, MYC seems to induce genomic instability by preventing DSB repair. What is left to determine is the precise mechanism by which this occurs, and the contribution that this makes to MYC-induced tumorigenesis.