The Role of the Core Non-Homologous End Joining Factors in Carcinogenesis and Cancer

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.

Targeting the DNA-PK complex: Its rationale use in cancer and HIV-1 infection

“…A line of evidence shows that Ku protein expression is increased in tumor cells versus normal cells in gastric and colorectal cancer [33,34]. The same correlation has been established between DNA-PKcs overexpression and carcinogenesis in prostate, lung, colorectal, esophageal and gastric cancer [31]. It can be postulated that predominance of an error-prone pathway such as NHEJ, may inhibit the accurate HR pathway and drives genomic instability.…”

“…Moreover, it has been shown that an overactive DNA damage repair in cancerous cells is associated with poor prognosis for patient. An over-efficient DNA damage repair provokes resistance to DNA damaging agent and is a barrier to treatment responsivity of malignancies [31].…”

“…These data showed the importance of fast repair by NHEJ during G1/S phase, even if other pathways of DSB repair exist. NHEJ is also necessary for development of innate immunity, namely V(D)J recombination and CSR [31].…”

“…In normal cells, tumorigenic effect of both downregulation or upregulation of NHEJ core factors suggest that a finely controlled balance exists between the various repair mechanisms, thus inhibiting cancer formation [31]. Indeed it could be deleterious to over or under activate the NHEJ pathway.…”

“…NHEJ appears to be one of the guardians of genome integrity in vertebrates, but this capacity is turned into a threat in the context of cancer. Many studies have shown a correlation between the increase of Ku and DNA-PKcs expressions and a high tumor proliferation rate, metastasis and poor prognosis of survival [31].…”