Cyclopurine DNA lesions and repair in individuals with bipolar disorder and their unaffected siblings

Oxidative stress plays a key role in bipolar disorder (BD). 8,5’-cyclopurine-2’-deoxynucleosides (cPUs), including R- and S-cdA, are tandem oxidative lesions that distort the DNA helix, impair replication and transcription, and are primarily repaired by the nucleotide excision repair (NER) pathway. To date, cPU levels and NER gene expressions have not yet been studied in BD. This study assessed cPU levels and the expression of NER genes (XPB, XPC, XPD, XPF, ERCC1, and CSB) in individuals with BD (n = 44), their unaffected siblings (n = 37), and healthy controls (HC; n = 46).

Urinary cPU levels were quantified using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Expression of NER pathway genes were assessed in peripheral blood samples using quantitative reverse transcription PCR. cPU levels were significantly elevated in both BD and sibling groups compared to HCs, with R-cdA concentrations highest in siblings. NER gene expressions were also increased: XPB, XPF, ERCC1, and CSB were upregulated in siblings, while XPC was elevated in both BD and sibling groups.

XPB, XPF, and CSB levels were significantly higher in siblings than in the BD group, whereas XPD expression was increased in the BD group compared to both siblings and HCs. Elevated nucleotide damage and increased NER gene expression in individuals with BD and their unaffected siblings support prior evidence implicating oxidative DNA damage and repair mechanisms in BD pathogenesis. The identification of cPU lesions and distinct NER expression patterns highlights additional molecular markers and suggests a potential familial vulnerability contributing to the development of BD.

The authors gratefully acknowledge the use of the services and facilities of the Koç University Research Center for Translational Medicine (KUTTAM). This work was supported by Dokuz Eylül University Scientific Research Project Scholarship (2021.KB.SAG.047) and Koç University. Department of Psychiatry, School of Medicine, Maltepe University, Istanbul, Turkey Department of Molecular Medicine, Institute of Health Sciences, Dokuz Eylul University, Izmir, Turkey Gamze Tuna, Selda Yılmaz & Nazlı Ecem Dal Bekar Vocational School of Health Services, Medical Laboratory Techniques Program, Dokuz Eylul University, Izmir, Turkey BioIzmir - Izmir Health Technologies Development and Accelerator Research and Application Center, Dokuz Eylul University, Izmir, Turkey Graduate School of Health Sciences, Koc University, Istanbul, Turkey İzel Cemre Akşahin, Aysan Eslami Abriz, Ceren Gör & Deniz Ceylan Research Center for Translational Medicine (KUTTAM), School of Medicine, Koc University, Istanbul, Turkey İzel Cemre Akşahin, İbrahim Fettahoğlu, Aysan Eslami Abriz, Ceren Gör & Deniz Ceylan Kartal Dr.

Lütfi Kırdar Training and Research Hospital, Istanbul, Turkey Department of Psychiatry, Haliç University School of Medicine, Istanbul, Turkey Chair of Proteomics and Bioanalytics, School of Life Sciences, Technical University of Munich, Munich, Germany Department of Medical Biochemistry, Sancaktepe Sehit Prof.Dr.Ilhan Varank Training and Research Hospital, Istanbul, Turkey Department of Psychiatry, School of Medicine, Marmara University, Istanbul, Turkey Department of Psychiatry, School of Medicine, Koc University, Istanbul, Turkey Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA Correspondence to Hidayet Ece Arat Çelik or Deniz Ceylan. The author declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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