Choices have consequences: the nexus between DNA repair pathways and genomic instability in cancer

DNA double strand breaks (DSBs) result as a consequence of the disassembly of the DNA double helix leading to the disruption of the stability of the genome. DSBs not only ensue from normal cellular metabolism, in the form of reactive oxygen species that can oxidize DNA bases [1, 2], but can also be generated during physiological processes like chromosome replication, meiotic recombination and DNA replication transcription collision [3–7]. Regardless of how DSBs are formed, faithful repair of these breaks are absolutely essential for maintenance of genome integrity. Failure to repair DSBs can lead to unwanted consequences, such as loss of genetic information, chromosomal rearrangements and even cell death. Cells have evolved with conserved recombination mediated genome editing pathways as a mean for repairing DSBs and restarting replication forks, thus allowing genome duplication to continue [8]. Recombination based mechanisms are crucial for both the repair and tolerance of DNA damage that vexes both strands of the double helix [9].

DNA double strand break repair (DSBR) pathways are generally classified based on whether sequence homology is used to join the broken DNA ends. Non-homologous end joining (NHEJ), which does not depend upon sequence homology, is the key repair pathway during the G0/G1 stages of the cell cycle [10]. During NHEJ, once a DSB is formed the broken ends are bound by Ku proteins (ku70 and ku80), which form a heterodimer and insulate the DNA ends from nucleolytic erosion [11, 12]. The Ku proteins foster direct ligation of the broken DNA ends by the specialized ligase complex Dnl4–Lif1 [12]. This complex can execute a blunt end ligation reaction on clean DNA ends, i.e. 3?-OH and 5?-phosphate groups. If the broken DNA ends are not clean, then further processing by nucleases and polymerases are necessary to ligate the loose ends [12]. However, in the midst of this process of genome editing, small deletions and insertions might be introduced at the junction site. This is why this pathway if often regarded to be an error-prone recovery mechanism [2, 13, 14].

In spite of the mutagenicity associated with NHEJ, its fast kinetics has a unique role in safeguarding genome integrity, particularly by suppressing chromosomal translocations [15]. A second NHEJ concomitant pathway often referred to as alternative-NHEJ (Alt-NHEJ), also known as Microhomology-mediated end joining (MMEJ), is another well-studied pathway for repairing DSBs in DNA [16]. The MMEJ repair pathway displays two diverging features from NHEJ; first is the use of 5–25 base pair (bp) microhomologous sequences during the alignment of the broken ends before religating them, and second is the slower kinetics of repair [15]. Much like NHEJ, MMEJ is frequently associated with chromosome anomalies such as deletions, translocations, inversions and other complex rearrangements. In contrast to NHEJ, there is an error-free DSBR pathway known as Homologous Recombination (HR) pathway where the cell employs a homologous DNA as template for the repair of the broken ends [17]. The homologous DNA may be a sister chromatid, a homologous chromosome or an ectopically located sequence. Further discussion on the detailed mechanisms of the repair systems mediated by NHEJ is beyond the scope of this review; instead we will focus on how DSBs are repaired error-free by HR, the various sub-types of HR and the molecular mechanisms regulating HR.