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Dietz, A.* ; Subedi, P.* ; Azimzadeh, O.* ; Duchrow, L.* ; Kaestle, F.* ; Paetzold, J.C.* ; Katharina Payer, S.* ; Hornhardt, S.* ; von Toerne, C. ; Hauck, S.M. ; Kempkes, B. ; Kuklik-Roos, C. ; Brandes, D.* ; Borkhardt, A.* ; Moertl, S.* ; Gomolka, M.*

The chromosome passenger complex (CPC) components and its associated pathways are promising candidates to differentiate between normosensitive and radiosensitive ATM-mutated cells.

Biomark. Insights 19:11772719241274017 (2024)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
BACKGROUND: Sensitivity to ionizing radiation differs between individuals, but there is a limited understanding of the biological mechanisms that account for these variations. One example of such mechanisms are the mutations in the ATM (mutated ataxia telangiectasia) gene, that cause the rare recessively inherited disease Ataxia telangiectasia (AT). Hallmark features include chromosomal instability and increased sensitivity to ionizing radiation (IR). OBJECTIVES: To deepen the molecular understanding of radiosensitivity and to identify potential new markers to predict it, human ATM-mutated and proficient cells were compared on a proteomic level. DESIGN: In this study, we analyzed 3 cell lines from AT patients, with varying radiosensitivity, and 2 cell lines from healthy volunteers, 24 hours and 72 hours post-10 Gy irradiation. METHODS: We used label-free mass spectrometry to identify differences in signaling pathways after irradiation in normal and radiosensitive individuals. Cell viability was initially determined by water soluble tetrazolium (WST) assay and DNA damage response was analyzed with 53BP1 repair foci formation along with KRAB-associated protein 1 (KAP1) phosphorylation. RESULTS: Proteomic analysis identified 4028 proteins, which were used in subsequent in silico pathway enrichment analysis to predict affected biological pathways post-IR. In AT cells, networks were heterogeneous at both time points with no common pathway identified. Mitotic cell cycle progress was the most prominent pathway altered after IR in cells from healthy donors. In particular, components of the chromosome passenger complex (INCENP and CDCA8) were significantly downregulated after 72 hours. This could also be verified at the mRNA level. CONCLUSION: Altogether, the most striking result was that proteins forming the chromosome passenger complex were downregulated after radiation exposure in healthy normosensitive control cells, but not in radiosensitive ATM-deficient cells. Thus, mitosis-associated proteins form an interesting compound to gain insights into the development and prediction of radiosensitivity.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter At Mutation ; Radiosensitivity ; Chromosome Passenger Complex ; Mass Spectrometry-based Proteomics; Mediated Abscission Checkpoint; Ataxia-telangiectasia; Radiation; Protein; Proteomics; Expression; Children; Inhibition; Anaphase; Damage
ISSN (print) / ISBN 1177-2719
e-ISSN 1177-2719
Zeitschrift Biomarker Insights
Quellenangaben Band: 19, Heft: , Seiten: , Artikelnummer: 11772719241274017 Supplement: ,
Verlag Sage
Verlagsort 1 Olivers Yard, 55 City Road, London Ec1y 1sp, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) CF Metabolomics & Proteomics (CF-MPC)
Research Unit Gene Vector (AGV)
Förderungen Bundesministerium fuer Bildung und Forschung (BMBF, Germany)