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Cancer and Radiosensitivity Syndromes: Is Impaired Nuclear ATM Kinase Activity the Primum Movens?

Laura El Nachef1, Elise Berthel1, Mélanie L Ferlazzo1

  • 1Inserm, U1296 Unit, Radiation: Defense, Health and Environment, Centre Léon-Bérard, 69008 Lyon, France.

Cancers
|December 23, 2022
PubMed

Insights

Genetic syndromes link high cancer risk and radiosensitivity through ATM kinase. Mutations in ATM phosphorylation substrates, often cytoplasmic, explain this connection, unifying cancer proneness and radiation sensitivity.

Area of Science:

  • Genetics
  • Molecular Biology
  • Radiation Oncology

Background:

  • Genetic syndromes often present with both increased cancer risk and clinical radiosensitivity.
  • The underlying molecular mechanisms connecting these two phenomena remain largely unknown.
  • Mutations in DNA repair, signaling, or cell cycle control genes are implicated in various cancer syndromes.

Purpose of the Study:

  • To explore a unified mechanistic model explaining the link between cancer proneness and radiosensitivity.
  • To investigate the role of ATM kinase and its phosphorylation substrates in this context.
  • To analyze how mutations affecting ATM substrates contribute to cancer and radiation sensitivity.

Main Methods:

  • Review and discussion of the radiation-induced nucleoshuttling of ATM kinase (RIANS) model.
  • Analysis of known cancer and radiosensitivity syndromes within the framework of the RIANS model.
  • Examination of the subcellular localization and phosphorylation status of mutated proteins.

Main Results:

  • The RIANS model provides a potential unified explanation for the co-occurrence of cancer proneness and radiosensitivity.
  • Mutated proteins responsible for major cancer and radiosensitivity syndromes are identified as ATM phosphorylation substrates.
  • These mutated proteins frequently exhibit cytoplasmic localization.

Conclusions:

  • The RIANS model offers a framework to understand how mutations in ATM substrates contribute to both cancer development and cellular radiosensitivity.
  • Cytoplasmic localization of mutated ATM substrates may be a key factor in these syndromes.
  • Further investigation into the RIANS model could elucidate the interplay between DNA damage response and cancer predisposition.
Keywords:
ATM proteincancergenetic syndromesradiosensitivity

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