Abstract
Background: In primary neuroblastoma, deletions on chromosome 11q are known to result in an increase in the total number of chromosomal breaks. Microhomology mediated-end joining (MMEJ) is an error-prone pathway for DNA double-strand break repair that is often upregulated in cancer. DLG2, a candidate tumor suppressor gene on chromosome 11q, has previously been implicated in DNA repair.Methods: We evaluated an association between MMEJ gene expression and neuroblastoma patient outcome, risk categorization, and 11q status using publicly available microarray data from independent neuroblastoma patient datasets. Functional studies were conducted using comet assay and H2AX phosphorylation in neuroblastoma cell lines and in the fruit fly with UVC-induced DNA breaks. Results: We show that the MMEJ genes PARP1 and FEN1 are over expressed in neuroblastoma and restoration of DLG2 impairs their gene and protein expression. When exposed to UVC radiation, cells with DLG2 over expression show less DNA fragmentation and induce apoptosis in a p53 S46 dependent manner. We could also confirm that DLG2 expression results in CHK1 phosphorylation consistent with previous reports of G2/M maintenance. Conclusions: Taken together, we show that DLG2 expression increases p53 mediated apoptosis in response to genotoxicity, by maintaining S317 CHK1 phosphorylation and reducing the DNA replication machinery.
Corruption of neuroblastoma patient derived xenografts with human T cell lymphoma
