Abstract
DNA double-strand breaks (DSBs) are deleterious DNA lesions that if left unrepaired or are misrepaired, potentially result in chromosomal aberrations, known drivers of carcinogenesis. Pathways that direct the repair of DSBs are traditionally believed to be guardians of the genome as they protect cells from genomic instability. The prominent DSB repair pathway in human cells is the non-homologous end joining (NHEJ) pathway, which mediates template-independent re-ligation of the broken DNA molecule and is active in all phases of the cell cycle. Its role as a guardian of the genome is supported by the fact that defects in NHEJ lead to increased sensitivity to agents that induce DSBs and an increased frequency of chromosomal aberrations. Conversely, evidence from tumors and tumor cell lines has emerged that NHEJ also promotes chromosomal aberrations and genomic instability, particularly in cells that have a defect in one of the other DSB repair pathways. Collectively, the data present a conundrum: how can a single pathway both suppress and promote carcinogenesis? In this review, we will examine NHEJ’s role as both a guardian and a disruptor of the genome and explain how underlying genetic context not only dictates whether NHEJ promotes or suppresses carcinogenesis, but also how it alters the response of tumors to conventional therapeutics.
Highlights
A myriad of elegant mechanisms have evolved that repair the vast number of DNA lesions an organism encounters each day
double-strand breaks (DSBs) are the most toxic DNA lesion, because if they are unrepaired, they can drive apoptosis or senescence, and if they are misrepaired they can lead to the generation of chromosomal aberrations, resulting in genomic instability, which can lead to tumorigenesis [2]
DNA-PKcs-dependent non-homologous end joining (NHEJ) plays a role in the formation of double minutes in colon cancer cells, which suggests that NHEJ may be responsible for the complete oncogenic potential of chromothripsis [39]
Summary
A myriad of elegant mechanisms have evolved that repair the vast number of DNA lesions an organism encounters each day. While the role of NHEJ in guarding the genome and protecting cells from agents that induce DSBs is well established, evidence has emerged that deregulated NHEJ may promote carcinogenesis by increasing genomic instability due to inappropriate repair. These dueling phenotypes for NHEJ-mediated DSB repair present a paradox: how can a single pathway be both a guardian, thereby preventing genomic instability and tumorigenesis, and a driver, thereby promoting genomic instability, and by proxy, carcinogenesis?. We will examine targeting NHEJ as a therapeutic cancer treatment strategy
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