Fibroblasts from Retinoblastoma Patients Show Radiosensitivity Linked to Abnormal Localization of the ATM Protein

Curr Eye Res. 2021 Apr;46(4):546-557. doi: 10.1080/02713683.2020.1808998. Epub 2020 Aug 30.


Purpose/aim of the study: Retinoblastoma (Rb) is a rare form of pediatric cancer that develops from retina cells. Bilateral and some unilateral forms of Rb are associated with heterozygous germline mutations of the (retinoblastoma 1) RB1 gene. RB1 mutations are also associated with a significant risk of secondary malignancy like head and neck tumors. Hence, to date, even if Rb patients are less subjected to radiotherapy to treat their primary ocular tumors, their healthy tissues may be exposed to significant doses of ionizing radiation during the treatment against their secondary malignancies with a significant risk of adverse tissue reactions (radiosensitivity) and/or radiation-induced cancer (radiosusceptibility). However, the biological role of the Rb protein in response to radiation remains misunderstood. Since the ataxia telangiectasia mutated (ATM) protein is a key protein of radiation response and since untransformed skin fibroblasts are a current model to quantify cellular radiosensitivity, we investigated here for the first time the functionality of the ATM-dependent signaling and repair pathway of the radiation-induced DNA double-strand breaks (DSB) in irradiated skin fibroblasts derived from Rb patients.

Materials and methods: The major biomarkers of the DSB repair and signaling, namely clonogenic cell survival, micronuclei, nuclear foci of the phosphorylated forms of the X variant of the H2A histone (γH2AX), the phosphorylated forms of the ATM protein (pATM) and the meiotic recombination 11 nuclease (MRE11) were assessed in untransformed skin fibroblasts derived from three Rb patients.

Results: Skin fibroblasts from Rb patients showed significant cellular radiosensitivity, incomplete DSB recognition, delay in the ATM nucleo-shuttling and exacerbated MRE11 nuclease activity. Treatment with statin and bisphosphonates led to significant complementation of these impairments.

Conclusions: Our findings strongly suggest the involvement of the ATM kinase in the radiosensitivity/radiosusceptibility phenotype observed in Rb cases.

Keywords: Rb; atm; dsb repair; radiosensitivity; retinoblastoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticholesteremic Agents / therapeutic use
  • Ataxia Telangiectasia Mutated Proteins / metabolism*
  • Bone Density Conservation Agents / therapeutic use
  • Cell Line
  • DNA Breaks, Double-Stranded
  • DNA Repair
  • Drug Combinations
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / radiation effects*
  • Humans
  • Pravastatin / therapeutic use
  • Radiation Dosage
  • Radiation Tolerance / physiology*
  • Retinal Neoplasms / pathology*
  • Retinoblastoma / pathology*
  • Retinoblastoma Binding Proteins / metabolism
  • Skin / drug effects
  • Skin / metabolism
  • Skin / radiation effects*
  • Ubiquitin-Protein Ligases / metabolism
  • X-Rays
  • Zoledronic Acid / therapeutic use


  • Anticholesteremic Agents
  • Bone Density Conservation Agents
  • Drug Combinations
  • RB1 protein, human
  • Retinoblastoma Binding Proteins
  • Zoledronic Acid
  • Ubiquitin-Protein Ligases
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Pravastatin