title: Distinct roles of Ape1 protein, an enzyme involved in DNA repair, in high or low linear energy transfer ionizing radiation-induced cell killing.
abstract: High linear energy transfer (LET) radiation from space heavy charged particles or a heavier ion radiotherapy machine kills more cells than low LET radiation, mainly because high LET radiation-induced DNA damage is more difficult to repair. Relative biological effectiveness (RBE) is the ratio of the effects generated by high LET radiation to low LET radiation. Previously, our group and others demonstrated that the cell-killing RBE is involved in the interference of high LET radiation with non-homologous end joining but not homologous recombination repair. This effect is attributable, in part, to the small DNA fragments (≤40 bp) directly produced by high LET radiation, the size of which prevents Ku protein from efficiently binding to the two ends of one fragment at the same time, thereby reducing non-homologous end joining efficiency. Here we demonstrate that Ape1, an enzyme required for processing apurinic/apyrimidinic (known as abasic) sites, is also involved in the generation of small DNA fragments during the repair of high LET radiation-induced base damage, which contributes to the higher RBE of high LET radiation-induced cell killing. This discovery opens a new direction to develop approaches for either protecting astronauts from exposure to space radiation or benefiting cancer patients by sensitizing tumor cells to high LET radiotherapy.
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia 30322 and.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia 30322 and.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia 30322 and.
authors.forename: Guangnan
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia 30322 and.
authors.forename: Xiangming
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia 30322 and.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia 30322 and.
authors.forename: Dongkyoo
authors.initials: D
authors.lastname: Park
authors.affiliation: Department of Health Physics and Diagnostic Sciences, University of Nevada, Las Vegas, Nevada 89154.
authors.forename: Francis A
authors.initials: FA
authors.lastname: Cucinotta
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia 30322 and.
authors.forename: David S
authors.initials: DS
authors.lastname: Yu
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia 30322 and.
authors.forename: Xingming
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia 30322 and.
authors.forename: William S
authors.initials: WS
authors.lastname: Dynan
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia 30322 and.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Doetsch
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia 30322 and. Electronic address: ywang94@emory.edu.
authors.forename: Ya
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D016923:Cell Death; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D053938:DNA Fragmentation; D045643:DNA Repair Enzymes / Q000378:metabolism; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D018499:Linear Energy Transfer; D000076228:MRE11 Homologue Protein; D008810:Mice, Inbred C57BL; D011833:Radiation Injuries, Experimental / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014965:X-Rays
chemical_list: D004268:DNA-Binding Proteins; C512689:Mre11a protein, mouse; D000076228:MRE11 Homologue Protein; C486216:Apex1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D045643:DNA Repair Enzymes
keywords: Ape1; DNA Damage; DNA Damage Response; DNA Enzyme; DNA Repair; DNA-binding Protein; High LET; Radiation Biology; Radiosensitivity