Defective double-strand DNA break repair and chromosomal translocations by MYC overexpression

Abstract

DNA repair mechanisms are essential for the maintenance of genomic integrity. Disruption of gene products responsible for DNA repair can result in chromosomal damage. Improperly repaired chromosomal damage can result in the loss of chromosomes or the generation of chromosomal deletions or translocations, which can lead to tumorigenesis. The MYC protooncogene is a transcription factor whose overexpression is frequently associated with human neoplasia. MYC has not been previously implicated in a role in DNA repair. Here we report that the overexpression of MYC disrupts the repair of double-strand DNA breaks, resulting in a several-magnitude increase in chromosomal breaks and translocations. We found that MYC inhibited the repair of ␥ irradiation DNA breaks in normal human cells and blocked the repair of a single double-strand break engineered to occur in an immortal cell line. By spectral karyotypic analysis, we found that MYC even within one cell division cycle resulted in a several-magnitude increase in the frequency of chromosomal breaks and translocations in normal human cells. Hence, MYC overexpression may be a previously undescribed example of a dominant mutator that may fuel tumorigenesis by inducing chromosomal damage.M any genes have been identified that are responsible for repairing DNA breaks and preserving chromosomal integrity (1-3). The loss of function of some of these genes can result in widespread chromosomal damage and contribute to tumorigenesis (4-6). In mammalian cells, double-strand DNA breaks (DSBs) are repaired by homology-directed recombination (HDR), nonhomologous end joining (NHEJ), and singlestrand annealing (SSA) (7). Defects in any of these repair mechanisms can result in chromosomal breaks, fusions, and translocations (8). Many human cancers exhibit characteristic chromosomal translocations thought to be responsible for tumorigenesis (9). The mechanisms by which these chromosomal translocations occur are not clear.MYC is a protooncogene that normally regulates cellular growth and proliferation and in some contexts induces apoptosis (10-12). MYC overexpression is thought to cause tumorigenesis by promoting unrestrained cellular proliferation and blocking differentiation. MYC overexpression may also contribute to tumorigenesis by inducing genomic destabilization (13-15). The genomic damage induced by MYC can be broadly grouped into two classes of abnormalities. First, overexpression of MYC induces loss of chromosomal integrity associated with chromosomal aberrations such as gene amplifications, double minutes, and fusions. Second, MYC overexpression can cause inappropriate DNA replication, resulting in endoreduplication.We speculated that the former type of genomic abnormalities might be caused by defects in the repair of DSBs. Here we demonstrate that MYC overexpression disrupts the repair of DSBs. Moreover, we show that MYC overexpression in normal human cells results in a several-magnitude increase in chromosomal breaks and translocations. Hence, MYC may be a previously undescribed ...

Inhibitory effect of c-Myc on p53-induced apoptosis in leukemia cells. Microarray analysis reveals defective induction of p53 target genes and upregulation of chaperone genes

“…This function has been recently found to play a prominent role in the tumor suppressor activity of p53 in vivo (Liu et al, 2004). Also, it is becoming increasingly clear that one consequence of deregulated MYC expression is genomic instability, which results in unscheduled DNA replication, gene rearrangements and chromosomal aberrations (Li and Dang, 1999;Kuschak et al, 2002;Sheen and Dickson, 2002;Karlsson et al, 2003). Thus, our data also support the hypothesis that deregulated MYC contributes to genomic instability in cells arrested by wild-type conformation p53.…”

Dysregulated TCL1 requires the germinal center and genome instability for mature B-cell transformation

“…Additionally, dysregulated MYC has been shown to impair double-stranded DNA break repair. 62,63 In some cell types, these changes are insufficient to induce transformation, indicating a need for complementing mutations. Studies of MYC transgenic mice using proviral insertional mutagenesis to tag interacting oncogenes identified several complementation groups for transformation.…”

DNA repair, genome stability and cancer: a historical perspective

“…The link between oncogene expression and DNA damage and/or its repair generated significant interest: for example, Myc expression in non-cancerous cells was shown to reduce DNA repair efficiency and induce p53 and its ATM-ATR dependent (but p14ARF-independent) phosphorylation 67,68 . Concurrently, p53 and p21 were shown to prevent cell proliferation when Cyclin E/Cdk2 was over-expressed and that this operated through an ATM/ATR-dependent and p14ARF independent mechanism 69 .…”