title: The repair of environmentally relevant DNA double strand breaks caused by high linear energy transfer irradiation--no simple task.
abstract: High linear energy transfer (LET) ionising radiation (IR) such as radon-derived alpha particles and high mass, high energy (HZE) particles of cosmic radiation are the predominant forms of IR to which humanity is exposed throughout life. High-LET forms of IR are established carcinogens relevant to human cancer, and their potent mutagenicity is believed, in part, to be due to a greater incidence of clustered DNA double strand breaks (DSBs) and associated lesions, as ionization events occur within a more confined genomic space. The repair of such DNA damage is now well-documented to occur with slower kinetics relative to that induced by low-LET IR, and to be more reliant upon homology-directed repair pathways. Underlying these phenomena is the relative inability of non-homologous end-joining (NHEJ) to adequately resolve high-LET IR-induced DSBs. Current findings suggest that the functionality of the DNA-dependent protein kinase (DNA-PK), comprised of the Ku70-Ku80 heterodimer and the DNA-PK catalytic subunit (DNA-PKcs), is particularly perturbed by high-LET IR-induced clustered DSBs, rendering DNA-PK dependent NHEJ less relevant to resolving these lesions. By contrast, the NHEJ-associated DNA processing endonuclease Artemis shows a greater relevance to high-LET IR-induced DSB repair. Here, we will review the cellular response to high-LET irradiation, the implications of the chronic, low-dose modality of this exposure and molecular pathways that respond to high-LET irradiation induced DSBs, with particular emphasis on NHEJ factors.
authors.affiliation: Southern Alberta Cancer Research Institute, Departments of Biochemistry & Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, Canada, T2N 4N1.
authors.forename: Shaun
authors.initials: S
authors.lastname: Moore
authors.affiliation: Southern Alberta Cancer Research Institute, Departments of Biochemistry & Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, Canada, T2N 4N1.
authors.forename: Fintan K T
authors.initials: FK
authors.lastname: Stanley
authors.affiliation: Southern Alberta Cancer Research Institute, Departments of Biochemistry & Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, Canada, T2N 4N1. Electronic address: A.Goodarzi@ucalgary.ca.
authors.forename: Aaron A
authors.initials: AA
authors.lastname: Goodarzi
mesh_terms: D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects*; D059766:DNA End-Joining Repair; D045643:DNA Repair Enzymes / Q000378:metabolism*; D051747:DNA-Activated Protein Kinase; D006801:Humans; D018499:Linear Energy Transfer; D011839:Radiation, Ionizing
chemical_list: D051747:DNA-Activated Protein Kinase; D045643:DNA Repair Enzymes
keywords: Alpha particles; Artemis; DNA double strand break repair; DNA-PK; HZE particles; High-LET radiation; Ku; Non-homologous end-joining