title: Functional regulation of the DNA damage-recognition factor DDB2 by ubiquitination and interaction with xeroderma pigmentosum group C protein.
abstract: In mammalian nucleotide excision repair, the DDB1-DDB2 complex recognizes UV-induced DNA photolesions and facilitates recruitment of the XPC complex. Upon binding to damaged DNA, the Cullin 4 ubiquitin ligase associated with DDB1-DDB2 is activated and ubiquitinates DDB2 and XPC. The structurally disordered N-terminal tail of DDB2 contains seven lysines identified as major sites for ubiquitination that target the protein for proteasomal degradation; however, the precise biological functions of these modifications remained unknown. By exogenous expression of mutant DDB2 proteins in normal human fibroblasts, here we show that the N-terminal tail of DDB2 is involved in regulation of cellular responses to UV. By striking contrast with behaviors of exogenous DDB2, the endogenous DDB2 protein was stabilized even after UV irradiation as a function of the XPC expression level. Furthermore, XPC competitively suppressed ubiquitination of DDB2 in vitro, and this effect was significantly promoted by centrin-2, which augments the DNA damage-recognition activity of XPC. Based on these findings, we propose that in cells exposed to UV, DDB2 is protected by XPC from ubiquitination and degradation in a stochastic manner; thus XPC allows DDB2 to initiate multiple rounds of repair events, thereby contributing to the persistence of cellular DNA repair capacity.
authors: Biosignal Research Center, Organization of Advanced Science and Technology, Kobe University, Kobe 657-8501, Japan Graduate School of Science, Kobe University, Kobe 657-8501, Japan.
authors: Syota
authors: S
authors: Matsumoto
authors: Friedrich Miescher Institute for Biomedical Research, CH-4058 Basel, Switzerland.
authors: Eric S
authors: ES
authors: Fischer
authors: National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors: Takeshi
authors: T
authors: Yasuda
authors: Global Research Cluster, RIKEN, Wako 351-0198, Japan.
authors: Naoshi
authors: N
authors: Dohmae
authors: Graduate School of Engineering Science, Osaka University, Toyonaka 560-8531, Japan.
authors: Shigenori
authors: S
authors: Iwai
authors: Advanced Medical Research Center, Nara Medical University, Kashihara 634-8521, Japan.
authors: Toshio
authors: T
authors: Mori
authors: Biosignal Research Center, Organization of Advanced Science and Technology, Kobe University, Kobe 657-8501, Japan.
authors: Ryotaro
authors: R
authors: Nishi
authors: Biosignal Research Center, Organization of Advanced Science and Technology, Kobe University, Kobe 657-8501, Japan.
authors: Ken-ichi
authors: K
authors: Yoshino
authors: Biosignal Research Center, Organization of Advanced Science and Technology, Kobe University, Kobe 657-8501, Japan Graduate School of Science, Kobe University, Kobe 657-8501, Japan.
authors: Wataru
authors: W
authors: Sakai
authors: Faculty of Science, Gakushuin University, Tokyo 171-8588, Japan.
authors: Fumio
authors: F
authors: Hanaoka
authors: Friedrich Miescher Institute for Biomedical Research, CH-4058 Basel, Switzerland.
authors: Nicolas H
authors: NH
authors: Thomä
authors: Biosignal Research Center, Organization of Advanced Science and Technology, Kobe University, Kobe 657-8501, Japan Graduate School of Science, Kobe University, Kobe 657-8501, Japan ksugasawa@garnet.kobe-u.ac.jp.
authors: Kaoru
authors: K
authors: Sugasawa
mesh_terms: D002460:Cell Line; D018360:Crystallography, X-Ray; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding; D054875:Ubiquitination; D014466:Ultraviolet Rays
chemical_list: C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; C086984:XPC protein, human
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