Abstract
Genomic instability is a common feature of cancer cells, which can result from aberrant DNA damage reaction (DDR). We and others showed that the well-known BCR-ABL1 fusion oncogene, the cause of chronic myeloid leukemia, induced an increased production of reactive oxygen species (ROS) and conferred therapeutic drug resistance by suppression of apoptotic signaling, prolonged G2/M arrest and stimulation of several pathways of DNA repair. However, to protect from apoptosis, cancer cells may tolerate some DNA lesions, which may increase genomic instability. Moreover, BCR/ABL1-stimulated DNA repair might be faulty, especially non-homologous end joining in its alternative forms. Normal DNA repair can remove DNA damage and prevent mutations, reducing genome instability, but on the other hand, due to its imprecise nature, it may increase genomic instability by increasing the ratio of mutagenic DNA lesions. The example of BCR-ABL1-expressing cells shows that DNA repair can both increase and decrease genomic instability of cancer cells and understanding the mechanism of the regulation of these opposite effects would be helpful in anticancer strategies.
Highlights
The t(9;22)(q34;q11) reciprocal chromosomal translocation produces the Philadelphia chromosome, containing juxtaposed fragments of the BCR and ABL1 genes, forming the BCR-ABL1 fusion gene
The expression of the gene can give three forms of BCR-ABL1 due to alternative splicing (Figure 1). This distinct chromosomal abnormality was causatively linked with chronic myeloid leukemia (CML), which was the first human cancer associated with chromosomal aberration
Results of experiments with BCR-ABL1-expressing transgenic mice showed that they had a higher spontaneous mutation rate than control animals, even before clinical onset of leukemia [52]
Summary
The t(9;22)(q34;q11) reciprocal chromosomal translocation produces the Philadelphia chromosome, containing juxtaposed fragments of the BCR and ABL1 genes, forming the BCR-ABL1 fusion gene. The expression of the gene can give three forms of BCR-ABL1 due to alternative splicing (Figure 1) This distinct chromosomal abnormality was causatively linked with chronic myeloid leukemia (CML), which was the first human cancer associated with chromosomal aberration (reviewed in [1]). Misrepair may be associated with recovering of DNA integrity, but DNA processed in this manner shows changes in the sequence, including lack of an original fragment, compared with native DNA In humans, this can be observed in non-homologous end joining (NHEJ) and its variants, in which DNA double strand breaks are repaired by processing DNA ends, making them a substrate to DNA ligase [21]. Genetic events are mainly DNA damages, which are not repaired or are misrepaired and turned into mutations supporting cancer transformation These mutations may be casual for cancer development, but do not necessarily contribute directly to genomic instability of cancer cells. When there are mutations in DNA repair genes, the chance of such events increase, contributing to increased genomic instability
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