title: ATDC (Ataxia Telangiectasia Group D Complementing) Promotes Radioresistance through an Interaction with the RNF8 Ubiquitin Ligase.
abstract: Induction of DNA damage by ionizing radiation (IR) and/or cytotoxic chemotherapy is an essential component of cancer therapy. The ataxia telangiectasia group D complementing gene (ATDC, also called TRIM29) is highly expressed in many malignancies. It participates in the DNA damage response downstream of ataxia telangiectasia-mutated (ATM) and p38/MK2 and promotes cell survival after IR. To elucidate the downstream mechanisms of ATDC-induced IR protection, we performed a mass spectrometry screen to identify ATDC binding partners. We identified a direct physical interaction between ATDC and the E3 ubiquitin ligase and DNA damage response protein, RNF8, which is required for ATDC-induced radioresistance. This interaction was refined to the C-terminal portion (amino acids 348-588) of ATDC and the RING domain of RNF8 and was disrupted by mutation of ATDC Ser-550 to alanine. Mutations disrupting this interaction abrogated ATDC-induced radioresistance. The interaction between RNF8 and ATDC, which was increased by IR, also promoted downstream DNA damage responses such as IR-induced γ-H2AX ubiquitination, 53BP1 phosphorylation, and subsequent resolution of the DNA damage foci. These studies define a novel function for ATDC in the RNF8-mediated DNA damage response and implicate RNF8 binding as a key determinant of the radioprotective function of ATDC.
authors.affiliation: Departments of Surgery, University of Michigan, Ann Arbor, Michigan 48109; Departments of Translational Oncology Program, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Huibin
authors.initials: H
authors.lastname: Yang
authors.affiliation: Departments of Translational Oncology Program, University of Michigan, Ann Arbor, Michigan 48109; Departments of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Phillip L
authors.initials: PL
authors.lastname: Palmbos
authors.affiliation: Departments of Surgery, University of Michigan, Ann Arbor, Michigan 48109; Departments of Translational Oncology Program, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Lidong
authors.initials: L
authors.lastname: Wang
authors.affiliation: Departments of Surgery, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Evelyn H
authors.initials: EH
authors.lastname: Kim
authors.affiliation: Departments of Translational Oncology Program, University of Michigan, Ann Arbor, Michigan 48109; Departments of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Gina M
authors.initials: GM
authors.lastname: Ney
authors.affiliation: Departments of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Departments of Translational Oncology Program, University of Michigan, Ann Arbor, Michigan 48109; Departments of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Jayendra
authors.initials: J
authors.lastname: Prasad
authors.affiliation: Departments of Surgery, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: David E
authors.initials: DE
authors.lastname: Misek
authors.affiliation: Departments of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Yu
authors.affiliation: Departments of Translational Oncology Program, University of Michigan, Ann Arbor, Michigan 48109; Departments of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Mats
authors.initials: M
authors.lastname: Ljungman
authors.affiliation: Departments of Surgery, University of Michigan, Ann Arbor, Michigan 48109; Departments of Translational Oncology Program, University of Michigan, Ann Arbor, Michigan 48109; Departments of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109. Electronic address: simeone@med.umich.edu.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Simeone
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000528:radiation effects; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D019313:BRCA1 Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011485:Protein Binding / Q000528:radiation effects; D054730:Protein Interaction Domains and Motifs; D011836:Radiation Tolerance / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000071857:Tumor Suppressor p53-Binding Protein 1; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C486521:RNF8 protein, human; D011994:Recombinant Proteins; C498301:TP53BP1 protein, human; C087296:TRIM29 protein, human; D014157:Transcription Factors; D000071857:Tumor Suppressor p53-Binding Protein 1; D044767:Ubiquitin-Protein Ligases
keywords: ATDC (ataxia-telangiectasia group D complementing gene); DNA damage response (DDR); DNA repair; DSB (double-strand break); E3 ubiquitin-protein ligase RNF8 (RNF8); IR (ionizing radiation); TRIM29; chromatin; protein-protein interaction; radiation