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DLG2 impairs dsDNA break repair and maintains genome integrity in neuroblastoma
University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR). (Translational Medicine TRIM)ORCID iD: 0000-0002-0471-6896
University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. (Translational Bioinformatics)ORCID iD: 0000-0001-7804-1177
University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR). (Translational Medicine TRIM)ORCID iD: 0000-0001-8962-0860
2022 (English)In: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 112, article id 103302Article in journal (Refereed) Published
Abstract [en]

Background

In primary neuroblastoma, deletions on chromosome 11q are known to result in an increase in the total number of chromosomal breaks. The DNA double-strand break repair pathways mediated by NHEJ are 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 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 NHEJ 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 over expression results in CHK1 phosphorylation consistent with previous reports of G2/M maintenance.

Conclusions

Taken together, we show that DLG2 over expression increases p53 mediated apoptosis in response to etoposide and UVC mediated genotoxicity and reduced DNA replication machinery.

Place, publisher, year, edition, pages
Elsevier, 2022. Vol. 112, article id 103302
Keywords [en]
DLG2, DNA, Damage, Neuroblastoma, Cancer
National Category
Cancer and Oncology Cell and Molecular Biology
Research subject
Translational Medicine TRIM; Bioinformatics
Identifiers
URN: urn:nbn:se:his:diva-20940DOI: 10.1016/j.dnarep.2022.103302ISI: 000782613400003PubMedID: 35217496Scopus ID: 2-s2.0-85124996325OAI: oai:DiVA.org:his-20940DiVA, id: diva2:1640646
Funder
Swedish Childhood Cancer Foundation, PR2016–0060Royal Physiographic Society in Lund
Note

CC BY 4.0

Corresponding author: E-mail address: simon.keane@his.se (S. Keane).

We thank the Swedish Childhood Cancer Fund [PR2016–0060], Jane and Dan Olsson Foundation [2020–29], Assar Gabrielssons Foundation [FB20–13], Nilsson-Ehle Endowments, Kungliga Fysiografiska sällskapet i Lund and University of Skövde for financial support.

Available from: 2022-02-25 Created: 2022-02-25 Last updated: 2022-12-16Bibliographically approved

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Keane, Simonde Weerd, Hendrik ArnoldEjeskär, Katarina

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