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Spatiotemporal 7q11.23 protein network analysis implicates the role of DNA repair pathway during human brain development.

ABSTRACT: Recurrent deletions and duplications of chromosome 7q11.23 copy number variants (CNVs) are associated with several psychiatric disorders. Although phenotypic abnormalities have been observed in patients, causal genes responsible for CNV-associated diagnoses and traits are still poorly understood. Furthermore, the targeted human brain regions, developmental stages, protein networks, and signaling pathways, influenced by this CNV remain unclear. Previous works showed GTF2I involved in Williams-Beuren syndrome, but pathways affected by GTF2I are indistinct. We first constructed dynamic spatiotemporal networks of 7q11.23 genes by combining data from the brain developmental transcriptome with physical interactions of 7q11.23 proteins. Topological changes were observed in protein-protein interaction (PPI) networks throughout different stages of brain development. Early and late fetal periods of development in the cortex, striatum, hippocampus, and amygdale were observed as the vital periods and regions for 7q11.23 CNV proteins. CNV proteins and their partners are significantly enriched in DNA repair pathway. As a driver gene, GTF2I interacted with PRKDC and BRCA1 to involve in DNA repair pathway. The physical interaction between GTF2I with PRKDC was confirmed experimentally by the liquid chromatography-tandem mass spectrometry (LC-MS/MS). We identified that early and late fetal periods are crucial for 7q11.23 genes to affect brain development. Our results implicate that 7q11.23 CNV genes converge on the DNA repair pathway to contribute to the pathogenesis of psychiatric diseases.

SUBMITTER: Chen L

PROVIDER: S-EPMC8050238 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:In this study, loss of expression of the fragile site-encoded Wwox protein was found to contribute to radiation and cisplatin resistance of cells, responses that could be associated with cancer recurrence and poor outcome. WWOX gene deletions occur in a variety of human cancer types, and reduced Wwox protein expression can be detected early during cancer development. We found that Wwox loss is followed by mild chromosome instability in genomes of mouse embryo fibroblast cells from Wwox-knockout mice. Human and mouse cells deficient for Wwox also exhibit significantly enhanced survival of ionizing radiation and bleomycin treatment, agents that induce double-strand breaks (DSBs). Cancer cells that survive radiation recur more rapidly in a xenograft model of irradiated breast cancer cells; Wwox-deficient cells exhibited significantly shorter tumor latencies vs Wwox-expressing cells. This Wwox effect has important consequences in human disease: in a cohort of cancer patients treated with radiation, Wwox deficiency significantly correlated with shorter overall survival times. In examining mechanisms underlying Wwox-dependent survival differences, we found that Wwox-deficient cells exhibit enhanced homology directed repair (HDR) and decreased non-homologous end-joining (NHEJ) repair, suggesting that Wwox contributes to DNA DSB repair pathway choice. Upon silencing of Rad51, a protein critical for HDR, Wwox-deficient cells were resensitized to radiation. We also demonstrated interaction of Wwox with Brca1, a driver of HDR, and show via immunofluorescent detection of repair proteins at ionizing radiation-induced DNA damage foci that Wwox expression suppresses DSB repair at the end-resection step of HDR. We propose a genome caretaker function for WWOX, in which Brca1-Wwox interaction supports NHEJ as the dominant DSB repair pathway in Wwox-sufficient cells. Taken together, the experimental results suggest that reduced Wwox expression, a common occurrence in cancers, dysregulates DSB repair, enhancing efficiency of likely mutagenic repair, and enabling radiation and cisplatin treatment resistance.

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Spatiotemporal 7q11.23 protein network analysis implicates the role of DNA repair pathway during human brain development.

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