The repair of environmentally relevant DNA double strand breaks caused by high linear energy transfer irradiation – No simple task
DNA Repair
Volume 17 , May 2014 , Pages 64-73
Author links open overlay panel Shaun Moore , Fintan K . T . Stanley , Aaron A . Goodarzi https :// doi . org / 10.1016 / j . dnarep . 2014.01.014 Get rights and content
Highlights
� • The majority of ionising radiation ( IR ) exposure to humanity occurs as high linear energy transfer ( LET ) IR .
� DNA damage from high-LET IR is more complex , where multiple lesions occur within a short distance , complicating DSB repair .
� • Non-homologous end-joining mediated DSB repair is constrained by increased complexity of high-LET IR associated DNA damage .
� • Comprehending the biological effects of high-LET IR is important for understanding the development and treatment of cancer .
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 IRinduced 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 .