Abnormal DNA end-joining activity in human head and neck cancer

Abstract

In human cells, DNA double-strand breaks (DSBs) are repaired primarily by the DNA end-joining (EJ) process and thus, abnormal DNA EJ activities lead to an accumulation of mutations and/or aneuploidy, resulting in genetic instability of cells. Since genetic instability is the hallmark of cancer cells, we studied the DNA EJ activities of normal, nonmalignant immortalized and malignant human epithelial cells to investigate the association between DNA EJ and carcinogenesis. We found a significant diminution of precise (error-free) DNA EJ activities in non-malignant immortalized human oral keratinocytes (HOK-16B) and human head and neck squamous cell carcinoma (HNSCC) cells compared to that in normal human oral keratinocytes (NHOK). Moreover, abnormal DNA EJ activities were detected exclusively in HOK-16B and HNSCC cells due to microhomology-mediated and non-microhomology-mediated end-joining activities in these cells. These data indicated that aberrant DNA EJ activity may be partly responsible for genetic instability and oncogenic transformation.

DNA polymerases δ and λ cooperate in repairing double-strand breaks by microhomology-mediated end-joining in Saccharomyces cerevisiae

“…In mammalian cells, this pathway of repair is known as alternative end-joining (Alt-EJ) and is often but not always associated with MHs, whereas in budding yeast, the commensurate pathway, MH-mediated end-joining (MMEJ), will typically use 5-25 bp of MH (6,7). These pathways are associated with genomic rearrangements, and cancer genomes show evidence of MH-mediated rearrangements (8)(9)(10)(11)(12). In addition, eukaryotic genomes contain many dispersed repetitive elements that can lead to genome rearrangements when recombination occurs between them (13)(14)(15)(16).…”

Ku70 predicts response and primary tumor recurrence after therapy in locally advanced head and neck cancer

“…NHEJ has been described as the predominant DSB repair mechanism in mammalian cells. 12 We hypothesized that the expression of NHEJ DNA repair (Ku70, Ku80 and DNA-PKcs) genes will influence tumor response to therapy on the basis of the following: (i) A high frequency of chromosomal translocations and alteration of double strand break (DSB) DNA repair in HNSCCs [13][14][15] ; (ii) Direct induction of DSBs by radiation 9 or indirectly by 5-FU 10,16 or cisplatin 8,11 ; (iii) The major importance of NHEJ in DSB repair, genomic stability maintenance and suppression of translocations in mammalian cells 17,18 ; (iv) An increased in vitro sensitivity to radiation by NHEJ protein inactivation and recovery of resistance by restoration of activity [19][20][21] and (v) Involvement of Ku70, Ku80 and DNA-PKcs in apoptotic signaling after radiation-or chemotherapy-induced DSBs.…”

Rad1, rad10 and rad52 Mutations Reduce the Increase of Microhomology Length during Radiation-Induced Microhomology-Mediated Illegitimate Recombination in Saccharomyces cerevisiae

“…Nonetheless, MHMR is a mutagenic pathway that generates large deletions and other genomic rearrangements, leading to human cancers and genetic diseases (13)(14)(15)(16)(17). Based on our data, it is plausible that part of the single-strand annealing apparatus interacts with other genetic factors that are involved in modulating the homology requirement in MHMR and allowing illegitimate recombination between a few base pairs of homology.…”

“…MHMR is independent of YKU70 and YKU80 and thus is distinct from the classical NHEJ pathway (7,(9)(10)(11)(12). MHMR is usually associated with deletions and other genomic rearrangements that have been implicated in human cancer and genetic diseases (13)(14)(15)(16)(17).…”