Abstract
In neuroblastoma, MYCN genomic amplification and segmental chromosomal alterations including 1p or 11q loss of heterozygocity and/or 17q gain are associated with progression and poor clinical outcome. Segmental alterations are the strongest predictor of relapse and result from unbalanced translocations attributable to erroneous repair of chromosomal breaks. Although sequence analysis of affected genomic regions suggests that these errors arise by nonhomologous end-joining (NHEJ) of DNA double-strand breaks (DSB), abnormalities in NHEJ have not been implicated in neuroblastoma pathogenesis. On this basis, the hypothesis that an error-prone mechanism of NHEJ is critical for neuroblastoma cell survival was tested. Plasmid-based DSB repair assays demonstrated efficient NHEJ activity in human neuroblastoma cells with repair products that were error-prone relative to nontransformed cells. Neuroblastoma cells derived from tumorigenic neuroblastic phenotypes had differential DNA repair protein expression patterns compared with nontumorigenic cells. Tumorigenic neuroblastoma cells were deficient in DNA ligase IV (Lig4) and Artemis (DCLRE1C), mediators of canonical NHEJ. Conversely, enzymes required for an error-prone alternative NHEJ pathway (alt-NHEJ), DNA Ligase IIIα (Lig3), DNA Ligase I (Lig1), and PARP1 protein were upregulated. Inhibition of Lig3 and Lig1 led to DSB accumulation and cell death, linking alt-NHEJ to cell survival in neuroblastoma. Neuroblastoma cells demonstrated sensitivity to PARP1 inhibition (PARPi) that paralleled PARP1 expression. In a dataset of human neuroblastoma patient tumors, overexpression of genes encoding alt-NHEJ proteins associated with poor survival. These findings provide an insight into DNA repair fidelity in neuroblastoma and identify components of the alt-NHEJ pathway as promising therapeutic targets.
Highlights
Neuroblastoma (NB), the most common extracranial solid tumor in children arises from neural crest precursors in the adrenal medulla and sympathetic neural ganglia
An erroneous mechanism of non-homologous end-joining (NHEJ) is the dominant double-strand breaks (DSB) repair pathway in NB cells Neuroblastoma tumors harbor segmental chromosomal alterations that are thought to arise from misrepair of DSB by the DNA end-joining process
There is increasing evidence that deregulation of NHEJ is a pathogenic factor in a number of cancers, including breast cancer, chronic myeloid leukemia (CML), and soft tissue sarcomas[34,35,36,37,38]
Summary
Neuroblastoma (NB), the most common extracranial solid tumor in children arises from neural crest precursors in the adrenal medulla and sympathetic neural ganglia. 50% of patients have high-risk disease that is refractory or relapse despite multimodality therapy. Such cases are commonly characterized by older age at presentation, tumor cell diploidy, and by recurrent chromosomal imbalances that predict prognosis. Sequence analysis of recurrent breakpoint regions in NB tumors provides evidence that segmental errors are generated by a DSB repair mechanism with characteristics of non-homologous end-joining (NHEJ)(11,12). This implies that segmental alterations could represent either an intact NHEJ mechanism processing abnormally high numbers of DSB or an underlying abnormality of DNA repair and maintenance [13]
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