title: α-N-methylation of damaged DNA-binding protein 2 (DDB2) and its function in nucleotide excision repair.
abstract: DDB2 exhibits a high affinity toward UV-damaged DNA, and it is involved in the initial steps of global genome nucleotide excision repair. Mutations in the DDB2 gene cause the genetic complementation group E of xeroderma pigmentosum, an autosomal recessive disease manifested clinically by hypersensitivity to sunlight exposure and an increased predisposition to skin cancer. Here we found that, in human cells, the initiating methionine residue in DDB2 was removed and that the N-terminal alanine could be methylated on its α-amino group in human cells, with trimethylation being the major form. We also demonstrated that the α-N-methylation of DDB2 is catalyzed by the N-terminal RCC1 methyltransferase. In addition, a methylation-defective mutant of DDB2 displayed diminished nuclear localization and was recruited at a reduced efficiency to UV-induced cyclobutane pyrimidine dimer foci. Moreover, loss of this methylation conferred compromised ATM (ataxia telangiectasia mutated) activation, decreased efficiency in cyclobutane pyrimidine dimer repair, and elevated sensitivity of cells toward UV light exposure. Our study provides new knowledge about the posttranslational regulation of DDB2 and expands the biological functions of protein α-N-methylation to DNA repair.
authors.affiliation: From the Environmental Toxicology Graduate Program and.
authors.forename: Qian
authors.initials: Q
authors.lastname: Cai
authors.affiliation: From the Environmental Toxicology Graduate Program and.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Fu
authors.affiliation: From the Environmental Toxicology Graduate Program and.
authors.forename: Zi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Chemistry, University of California, Riverside, California 92521-0403.
authors.forename: Nanqin
authors.initials: N
authors.lastname: Gan
authors.affiliation: Department of Chemistry, University of California, Riverside, California 92521-0403.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Dai
authors.affiliation: From the Environmental Toxicology Graduate Program and Department of Chemistry, University of California, Riverside, California 92521-0403 yinsheng.wang@ucr.edu.
authors.forename: Yinsheng
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D001483:Base Sequence; D015153:Blotting, Western; D017931:DNA Primers; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D008745:Methylation; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000596:Amino Acids; C117669:DDB2 protein, human; D017931:DNA Primers; D004268:DNA-Binding Proteins
keywords: DNA Damage; DNA Repair; DNA-binding Protein; Mass Spectrometry (MS); Posttranslational Modification (PTM)
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