Not Black or White but Shades of Gray: Homologous Recombination Deficiency as a Continuous Variable Modulated by RNF168

In this issue of Cancer Research, the study by Krais and colleagues underscores that DNA damage repair by homologous recombination (HR) is not an all-or-nothing phenomenon, but that HR competency comes on a spectrum, ranging from complete deficiency to proficiency. Residual low-level HR in BRCA1-mutant cancer cells turns out to be critically important for their survival and is afforded by low levels of Histone 2A (H2A) ubiquitination resulting from lowered RNF168 levels. The findings raise the possibility that, if ubiquitination of H2A could be enforced by inhibition of deubiquitinases, residual HR in BRCA1mt cells might be extinguished. Extinction of residual HR might improve the therapeutic efficacy of the emerging inhibitors of DNA damage repair. The development of methods to measure HR directly and quantitatively is crucial to develop this field.See related article by Krais et al., p. 2848.