title: NBS1 recruits RAD18 via a RAD6-like domain and regulates Pol η-dependent translesion DNA synthesis.
abstract: Translesion DNA synthesis, a process orchestrated by monoubiquitinated PCNA, is critical for DNA damage tolerance. While the ubiquitin-conjugating enzyme RAD6 and ubiquitin ligase RAD18 are known to monoubiquitinate PCNA, how they are regulated by DNA damage is not fully understood. We show that NBS1 (mutated in Nijmegen breakage syndrome) binds to RAD18 after UV irradiation and mediates the recruitment of RAD18 to sites of DNA damage. Disruption of NBS1 abolished RAD18-dependent PCNA ubiquitination and Polη focus formation, leading to elevated UV sensitivity and mutation. Unexpectedly, the RAD18-interacting domain of NBS1, which was mapped to its C terminus, shares structural and functional similarity with the RAD18-interacting domain of RAD6. These domains of NBS1 and RAD6 allow the two proteins to interact with RAD18 homodimers simultaneously and are crucial for Polη-dependent UV tolerance. Thus, in addition to chromosomal break repair, NBS1 plays a key role in translesion DNA synthesis.
authors: Radiation Biology Center, Kyoto University, Kyoto 606-8501, Japan.
authors: Hiromi
authors: H
authors: Yanagihara
authors: Junya
authors: J
authors: Kobayashi
authors: Satoshi
authors: S
authors: Tateishi
authors: Akihiro
authors: A
authors: Kato
authors: Shinya
authors: S
authors: Matsuura
authors: Hiroshi
authors: H
authors: Tauchi
authors: Kouichi
authors: K
authors: Yamada
authors: Jun
authors: J
authors: Takezawa
authors: Kaoru
authors: K
authors: Sugasawa
authors: Chikahide
authors: C
authors: Masutani
authors: Fumio
authors: F
authors: Hanaoka
authors: Corry M
authors: CM
authors: Weemaes
authors: Toshio
authors: T
authors: Mori
authors: Lee
authors: L
authors: Zou
authors: Kenshi
authors: K
authors: Komatsu
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D014466:Ultraviolet Rays; D000099270:Y-Family DNA Polymerases
chemical_list: D018797:Cell Cycle Proteins; D004247:DNA; D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D044763:Ubiquitin-Conjugating Enzymes; C466108:Nijmegen breakage syndrome 1 protein, mouse; C485953:Rad18 protein, mouse; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases