Genes affecting ionizing radiation survival identified through combined exome sequencing and functional screening

Area of Science:

• Genetics
• Molecular Biology
• Cancer Research

Background:

• Genetic syndromes causing DNA damage sensitivity offer insights into genome stability.
• These syndromes can inform cancer therapy development.
• Understanding novel genetic causes is crucial for diagnosing and treating complex conditions.

Purpose of the Study:

• To investigate the genetic basis of hypersensitivity to ionizing radiation in individuals without a clear diagnosis.
• To identify novel genes and pathways involved in DNA damage response.
• To explore potential gene-gene interactions contributing to radiation sensitivity.

Main Methods:

• Exome sequencing was performed on 51 unrelated individuals with unexplained hypersensitivity to ionizing radiation and associated symptoms.
• Variant identification, computational deleteriousness predictions, and functional screening (siRNA in U2OS cells) were employed.
• Subjects were categorized based on identified genetic variants and their functional impact.

Main Results:

• Two subjects had bi-allelic loss-of-function variants in known DNA damage response (DDR) genes.
• Eight subjects had single loss-of-function variants in known DDR genes, with six also having predicted deleterious variants in other DDR-related genes.
• Three subjects had mutations in genes not obviously linked to DNA damage, but siRNA targeting these genes increased radiation sensitivity in U2OS cells.

Conclusions:

• The study identified both known and potentially novel genetic contributors to ionizing radiation sensitivity.
• Gene-gene interactions may play a significant role in an individual's response to DNA damage.
• Genes not traditionally associated with DNA damage response may influence sensitivity, opening new avenues for research and therapy.