Abstract
Artemis is an endonuclease responsible for breaking hairpin DNA strands during immune system adaptation and maturation as well as the processing of potentially toxic DNA lesions. Thus, Artemis may be an important target in the development of anticancer therapy, both for the sensitization of radiotherapy and for immunotherapy. Despite its importance, its structure has been resolved only recently, and important questions concerning the arrangement of its active center, the interaction with the DNA substrate, and the catalytic mechanism remain unanswered. In this contribution, by performing extensive molecular dynamic simulations, both classically and at the hybrid quantum mechanics/molecular mechanics level, we evidenced the stable interaction modes of Artemis with a model DNA strand. We also analyzed the catalytic cycle providing the free energy profile and key transition states for the DNA cleavage reaction.
Highlights
Artemis is an endonuclease [1,2,3] that plays a fundamental role in processing DNA strands in immune system cells, allowing their recombination and the maturation of the immune response
V(D)J [4,5] is the mechanism through which immune system cells assemble variable (V), diversity (D), and joining (J) gene sequences responsible for the production of immunoglobulins (Igs) and T cell receptors that can recognize a large number of antigens
We first performed an molecular dynamics (MD) simulation of the unbound wild-type form of the catalytic domain of human Artemis starting from the structure reported by Karim et al [20]
Summary
Artemis is an endonuclease [1,2,3] that plays a fundamental role in processing DNA strands in immune system cells, allowing their recombination and the maturation of the immune response. Non-functional mutations of Artemis have been correlated with an increased radiosensitivity [10] of B and T cells, suggesting its participation to the strand break repair machinery [14]. It has been shown in cellular models that Artemis is recruited to the site of DNA damage and acts in a way that is similar to non-homologous end-joining pathways to assure repair [15,16]. The interplay between DNA repair and immune system maturation has been highlighted, in the sense that DNA repair machinery can participate in the last steps of the V(D)J process [10]
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