DNA double-strand breaks (DSB) are considered to be a severe form of DNA damage, because if left unrepaired, they can cause a cell death and, if misrepaired, they can lead to genomic instability and, ultimately, the development of cancer in multicellular organisms. The budding yeast Saccharomyces cerevisiae repairs DSB primarily by homologous recombination (HR), despite the presence of the KU70, KU80, DNA ligase IV and XRCC4 homologues, essential factors of the mammalian non-homologous end-joining (NHEJ) machinery. S. cerevisiae, however, lacks clear DNA-PKcs and ARTEMIS homologues, two important additional components of mammalian NHEJ. On the other hand, S. cerevisiae is endowed with a regulatory NHEJ component, Nej1, which has not yet been found in other organisms. Furthermore, there is evidence in budding yeast for a requirement for the Mre11/Rad50/Xrs2 complex for NHEJ, which does not appear to be the case either in Schizosaccharomyces pombe or in mammals. Here, we comprehensively describe the functions of all the S. cerevisiae NHEJ components identified so far and present current knowledge about the NHEJ process in this organism. In addition, this review depicts S. cerevisiae as a powerful model system for investigating the utilization of either NHEJ or HR in DSB repair.

The nucleotide excision repair (NER) pathway is activated in response to a broad spectrum of DNA lesions, including bulky lesions induced by platinum-based chemotherapeutic agents. Expression levels of NER factors and resistance to chemotherapy has been examined with some suggestion that NER plays a role in tumour resistance; however, there is a great degree of variability in these studies. Nevertheless, recent clinical studies have suggested Xeroderma Pigmentosum group A (XPA) protein, a key regulator of the NER pathway that is essential for the repair of DNA damage induced by platinum-based chemotherapeutics, as a potential prognostic and predictive biomarker for response to treatment. XPA functions in damage verification step in NER, as well as a molecular scaffold to assemble other NER core factors around the DNA damage site, mediated by protein–protein interactions. In this review, we focus on the interacting partners and mechanisms of regulation of the XPA protein. We summarize clinical oncology data related to this DNA repair factor, particularly its relationship with treatment outcome, and examine the potential of XPA as a target for small molecule inhibitors.