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preliminary prostate toxicity

LncDNAH5 linked a prostate radiotoxicity risk variant to altered DNA repair

The rs7720298 risk allele increased LncDNAH5 expression, promoting TP53BP1 degradation and worsening radiation-induced bladder injury in mice.

RadOncToday · ·1 min read

KEY POINTS

  • The work investigated a previously identified radiogenomic signal from a GWAS meta-analysis of 1,638 prostate cancer patients. The rs7720298 locus had been associated with reduced urinary stream two years after radiotherapy, with an odds ratio of 2.71 (95% CI 1.90–3.86; p = 3.21 × 10⁻⁸).
  • Prostate tissue from 40 East Asian men with benign prostatic hyperplasia included 34 C/C and six C/G genotypes. LncDNAH5 expression was significantly higher in available C/G samples than C/C samples, and CRISPR introduction of the G allele into C/C bladder epithelial cells increased LncDNAH5 without altering the nearby protein-coding DNAH5 gene.
  • LncDNAH5 overexpression reduced the DNA double-strand break repair protein TP53BP1, including fewer TP53BP1 foci after 2 Gy irradiation. Functional experiments indicated a shift away from non-homologous end joining toward homologous recombination and greater residual DNA damage after irradiation.
  • Mechanistically, LncDNAH5 promoted ubiquitin-dependent TP53BP1 degradation by facilitating interaction with MDM2. RNA immunoprecipitation showed approximately 7-fold and 70-fold enrichment of LncDNAH5 relative to MDM2-only and empty-vector controls, while TP53BP1 immunoprecipitation produced approximately 220-fold enrichment in LncDNAH5-overexpressing cells.
  • The MDM2 antagonist Nutlin-3 partially restored TP53BP1 stability and foci formation and mitigated the excess DNA damage associated with LncDNAH5 overexpression, supporting MDM2 as a functional mediator rather than simply a correlated protein.
  • In a bladder-specific LncDNAH5 transgenic mouse model, a single 12 Gy bladder irradiation increased urination frequency in both wild-type and transgenic animals by day 6. Wild-type mice subsequently recovered, whereas transgenic mice worsened by day 12 and remained above baseline at day 18.
  • Transgenic bladders also showed increased Gm-csf, Il-4 and Il-10 expression, greater neutrophil infiltration at one week, increased collagen deposition at one month, and higher Doppler-measured bladder-wall perfusion. The mouse model used an acute single-dose exposure rather than clinical fractionated prostate radiotherapy, limiting direct translation.

CLINICAL TAKEAWAY

The study provides a plausible mechanistic bridge between a prostate radiotherapy GWAS signal and normal-tissue radiosensitivity through the rs7720298–LncDNAH5–MDM2–TP53BP1 pathway. It strengthens the biological rationale for radiogenomic toxicity prediction, but neither rs7720298 nor LncDNAH5 is ready for clinical risk stratification or treatment modification.

SOURCE

International Journal of Radiation Oncology, Biology, Physics