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.

Keywords: DSB repair; NHEJ; cancer; cancer therapy; carcinogenesis; genomic instability.

Figure 1

General NHEJ Mechanism. (A) and (B). A DNA double strand break (DSB) is induced and is quickly bound by the Ku heterodimer; (C). Ku70/80 serves as a scaffold to recruit the NHEJ machinery to the DSB; (D). If the DSB ends cannot be ligated, they will be processed by specific DNA end processing factors; (E). The DSB is ligated by DNA Ligase IV and NHEJ is complete.

Figure 2

NHEJ-mediated chromosomal aberrations. (A). If the two junctions of the DSB (1.) are incompatible for ligation (2.), they will be processed (3.), which can result in small deletions, insertions via the fill-in polymerases, or indels (designated as a red rectangle) (4.); (B). Homologous recombination typically directs the repair of one-ended DSBs, which arise when a replication fork collapses or when the replication fork hits a DNA lesion (designated as a red star) (1.). However, if NHEJ attempts to repair one-ended DSBs (2.), it will do so by using a distal DSB to mediate repair (3.), resulting in a translocation (4.); (C). A single catastrophic event, termed chromothripsis (1.), can produce multiple DSBs of a chromosome (2.), which are then randomly rejoined by NHEJ in a chaotic genomic structure (3.).