Dear Colleagues,

Genomic DNA is constantly under threat from endogenous and exogenous DNA-damaging agents. To promote genomic stability, mammalian cells have evolved highly-conserved DNA damage-sensor mechanisms that can induce; (a) induction of apoptosis to eliminate heavily damaged cells; (b) transcriptional response, which causes changes in the transcriptional profile that may promote cell survival; (c) DNA damage tolerance;  (d) activation of DNA damage checkpoints and modulation of cell cycle progression to allow time for DNA repair; and/or  (e) initiation of DNA repair to restore genomic stability. Therefore, to maintain genomic stability, cells have developed highly-conserved and robust mechanisms to detect and repair DNA damage. Given the wide spectrum of DNA-damaging lesions that can promote genomic instability, it is perhaps not surprising that multiple pathways exist in cells for effective DNA repair. These include direct repair, base excision repair, nucleotide excision repair, mis-match repair, inter strand cross link repair, and double strand break repair. Recent advances in molecular biology have, not only provided unprecedented insights, but have also identified additional mechanisms that promote genomic integrity.

Failure to initiate a cellular response to DNA damage can lead to the accumulation of mutagenic lesions, which are associated with ageing, neurological disorders, and cancer. Furthermore, germline mutations in DNA repair genes lead to cancer predisposing syndromes. Conversely, in established sporadic solid tumor, oxidative stress and hypoxia can induce DNA repair up-regulation as an adaptive survival response, which can promote an aggressive phenotype. Moreover, such DNA repair upregulated tumors can also effectively process DNA damage caused by chemotherapy and radiation frequently used in cancer therapy. In fact, the capacity of cancer cells to identify and repair the damage caused by therapeutic assault is a key driver of acquired resistance and therefore limits the effectiveness of these conventional treatment approaches. Interesting emerging evidence in tumor biology is that RNA-processing pathways may participate in DNA Damage Response (DDR) and that defects in these regulatory connections are associated with genomic instability of cancers. Interactomic studies, for instance, showed that many BER proteins are associated with those involved in RNA metabolism, ncRNA processing and transcriptional regulation, including within the nucleolus, proving a substantial role of the interactome network in determining their non-canonical functions in tumor cells. Perhaps these new insights of DNA repair enzymes, along with their emerging function in RNA-decay, may explain additional mechanisms and role of DNA repair enzymes in tumor development and chemoresistance and may explain the long-time mystery.

Pharmacological targeting of DNA repair can increase the efficacy of current treatments and overcome the risk of therapeutic resistance. Furthermore, the concept of synthetic lethality, whereby the loss of function of either one of two inter-related genes is not lethal, but loss of both genes results in cell death, provides an exciting new platform for pharmacological targeting of DNA repair. The recent clinical approval of PARP inhibitors in BRCA germ-line deficient breast and ovarian cancer patients as well as in platinum sensitive ovarian cancers provides a new approach to personalize cancer therapy. Newer synthetic lethality approaches targeting other DNA repair factors are also highly desirable and have the potential to expand therapeutic opportunities in cancer.

In this Special Issue, we focus on recent advances in molecular biology of DNA repair, as well as its relevance as a key prognostic, predictive, and therapeutic targets in cancer.

Prof. Srinivasan Madhusudan
Prof. Dr. Gianluca Tell
Guest Editors

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• DNA repair
• biology
• cancer
• prognosis
• drug targets
• synthetic lethality