LncDNAH5 Regulates Radiotherapy-Induced Toxicity via MDM2-Mediated Degradation of TP53BP1.

Authors

Xin Sun, Antao Dong, Liangliang Li, Ying Tsai, Xue-Ru Wu, Sarah Kerns, Brian Marples, Chen Lei, Vera Gorbunova, Yin Sun, Tao Zhang, Yuhchyau Chen

Published in

International journal of radiation oncology, biology, physics. Aug 01, 2026. Epub Aug 01, 2026.

Abstract

Radiation therapy (RT) cures many patients with localized prostate cancer, but late urinary toxicity impairs quality of life and can limit dose escalation for better RT efficacy. Understanding the mechanistic bases of radiation toxicity is critical for designing effective treatment strategies to benefit prostate cancer survivors. Genome-wide association studies (GWAS) have shown that genetic susceptibility can influence toxicity risk. A GWAS of reduced urinary stream two years after RT identified rs7720298 tagging a risk locus, but the mechanism through which this SNP acts is unclear. We performed integrative bioinformatics and molecular studies that identified a nearby long non-coding RNA, LncDNAH5, whose expression is influenced by rs7720298 in human tissues, and we hypothesized it mediates RT responses. In cultured cells, LncDNAH5 suppressed the DNA repair factor TP53BP1, thus favoring homologous recombination (HR) over non-homologous end joining (NHEJ). Mechanistically, LncDNAH5 enhanced MDM2-dependent ubiquitination and degradation of TP53BP1 by promoting formation of an MDM2-TP53BP1 complex; MDM2 antagonist Nutlin-3 attenuated these effects. In vivo, a bladder-specific LncDNAH5 overexpression mouse model exhibited exacerbated RT-induced inflammatory and fibrotic responses, consistent with a heightened urothelial radiosensitivity. Together, these data support a rs7720298/LncDNAH5/MDM2/TP53BP1 axis that modulates DNA repair choice and tissue response to radiation. Clinically, LncDNAH5 expression and rs7720298 genotype may serve as complementary biomarkers to identify patients at risk for late urinary toxicity and to guide early intervention and personalized radioprotective strategies for better patient outcomes.

PMID:
42542301
Bibliographic data and abstract were imported from PubMed on 02 Aug 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.