How cancer cells hijack DNA double-strand break repair pathways to gain genomic instability

Abstract

DNA DSBs (double-strand breaks) are a significant threat to the viability of a normal cell, since they can result in loss of genetic material if mitosis or replication is attempted in their presence. Consequently, evolutionary pressure has resulted in multiple pathways and responses to enable DSBs to be repaired efficiently and faithfully. Cancer cells, which are under pressure to gain genomic instability, have a striking ability to avoid the elegant mechanisms by which normal cells maintain genomic stability. Current models suggest that, in normal cells, DSB repair occurs in a hierarchical manner that promotes rapid and efficient rejoining first, with the utilization of additional steps or pathways of diminished accuracy if rejoining is unsuccessful or delayed. In the present review, we evaluate the fidelity of DSB repair pathways and discuss how cancer cells promote the utilization of less accurate processes. Homologous recombination serves to promote accuracy and stability during replication, providing a battlefield for cancer to gain instability. Non-homologous end-joining, a major DSB repair pathway in mammalian cells, usually operates with high fidelity and only switches to less faithful modes if timely repair fails. The transition step is finely tuned and provides another point of attack during tumour progression. In addition to DSB repair, a DSB signalling response activates processes such as cell cycle checkpoint arrest, which enhance the possibility of accurate DSB repair. We consider the ways by which cancers modify and hijack these processes to gain genomic instability.

Ligase I and ligase III mediate the DNA double-strand break ligation in alternative end-joining

“…Although NHEJ is simpler and faster than HR, repair by NHEJ often leads to change of sequences in the repair junctions via deletion, insertion, and mutations. Most importantly, NHEJ can also directly ligate two distant DSBs (both in cis-and transchromosomes), therefore leading to chromosomal deletions and translocations that are tightly linked to the genome evolution and carcinogenesis (3).…”

Oncogenic transformation of normal breast epithelial cells co-cultured with cancer cells

“…If not, the damage will lead to cell death via lethal chromosomal aberrations or direct induction of apoptosis [39]. The different radiation responses observed in C2 and C3 cells may be due to the fact that cancer cells often harbor a reduced repertoire of DNA repair signaling capabilities compared to normal cells, and in some cases cancers also upregulate mutagenic repair pathways that drive oncogenesis [40]. Co-cultured cells transformed from normal cell may still have the normal DNA repair mechanism.…”

Downregulation of eukaryotic initiation factor 4A1 improves radiosensitivity by delaying DNA double strand break repair in cervical cancer

“…Base damage, DNA strand cross-linking and single strand breaks are often repaired successfully, however, DSB repair tends to result in gene mutations or genomic instability (26)(27)(28). It has been reported that γ-H2AX forms at the DSB site in response to DNA damage caused by ionizing radiation, and that each foci of γ-H2AX corresponds to one DSB (29)(30)(31)(32)(33)(34).…”