LncDNAH5 Regulates Radiation Therapy-Induced Toxicity via MDM2-Mediated Degradation of TP53BP1

Radiation therapy (RT) is a primary curative treatment for prostate cancer, but its biophysical effects are not cancer cell-specific, often leading to toxicity in adjacent tissues. Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with RT-induced toxicities. Specifically, rs7720298, located in intron 30 of the DNAH5 gene, is significantly linked to late urinary toxicity, notably a reduced urinary stream two years post RT compared to baseline. However, the molecular and cellular mechanisms underlying this association remain unclear.

Through bioinformatics analysis, we identified LncDNAH5, a long non-coding RNA close to the rs7720298 locus that regulates its expression. Using human tissues and cell lines, we examined LncDNAH5 expression and the functional impact of rs7720298 allelic variation. A mouse models with bladder-specific overexpression of LncDNAH5 was employed to evaluate its role in radiation-induced toxicity.

LncDNAH5 regulates DNA repair pathway choice by downregulating TP53BP1, thereby suppressing non-homologous end joining (NHEJ) and promoting homologous recombination (HR). It does so likely through enhancing MDM2-mediated ubiquitination and degradation of TP53BP1 by promoting physical complex formation between these two proteins. These effects were attenuated by Nutlin-3 treatment. Bladder-specific overexpression of LncDNAH5 in the mouse exacerbated radiation-induced inflammatory and fibrotic responses.

The rs7720298 variant can influence RT-induced toxicity via regulation of LncDNAH5 expression. Both LncDNAH5 expression levels and rs7720298 genotyping may serve as predictive biomarkers for late urinary toxicity, facilitating early intervention and personalized radioprotective strategies to improve outcomes in prostate cancer patients.