The RING finger protein RNF8 recruits UBC13 for lysine 63‐based self polyubiquitylation

Plans, Vanessa; Scheper, Johanna; Soler, Marta; Loukili, Noureddine; Okano, Yukio; Thomson, Timothy M.

doi:10.1002/jcb.20587

Cited by 91 publications

(102 citation statements)

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“…Constitutive nuclear localization of RNF8 requires the FHA, RING-finger and coiled-coil domains We had determined previously that staining of HeLa cells with an antibody specific for RNF8 showed a nuclear localization in the majority of cells (Plans et al, 2006). To study the contribution of each domain of RNF8 to this nuclear localization, HA-tagged fulllength and partial constructs of RNF8 were generated ( Figure 1).…”

Section: Resultsmentioning

confidence: 99%

“…Although FHA domains were initially identified in transcription factors and in protein kinases, they are also present in other proteins that define or regulate checkpoints (Hofmann and Bucher, 1995). In eukaryotes, only five proteins bear a FHA domain along with a RING-finger domain, CHFR and RNF8 in metazoans and SpDma1, ScDma1 and ScDma2 in yeasts (Murone and Simanis, 1996;Scolnick and Halazonetis, 2000;Guertin et al, 2002a;Plans et al, 2006). All these proteins, except for RNF8 that has not been previously studied in the context of the cell cycle, have been shown to regulate mitotic checkpoints.…”

Section: Introductionmentioning

confidence: 99%

“…RNF8 is a ubiquitin ligase that recruits several ubiquitin-conjugating enzymes, including the heterodimeric E2 enzyme UBC13-UEV that promotes the elongation of polyubiquitin chains based on Lys 63 on the ubiquitin polypeptide (Ito et al, 2001;Plans et al, 2006). RNF8 was previously reported to interact with the nuclear receptor RXRa and to enhance its transcriptional activity (Takano et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Regulation of mitotic exit by the RNF8 ubiquitin ligase

2007

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RNF8 is a ubiquitin ligase with a FHA domain near its N terminus, and a RING-finger domain at its C terminus, through which it recruits several ubiquitin-conjugating enzymes. In metazoans, only the mitotic checkpoint regulator CHFR shares this domain architecture. Here we show that RNF8 is a nuclear protein that follows a cellcycle-dependent turnover, reaching its highest levels in mitosis, followed by a strong decline in late mitotic stages. Overexpression of RNF8 caused a delay in cytokinesis and the frequent appearance of aberrant mitotic figures. These effects were dependent on the ubiquitin ligase activity of RNF8, since they were significantly attenuated when a RING-finger mutant, inactive as an E3, was overexpressed. Depletion of RNF8 also caused a delay in the exit from the mitotic arrest induced by nocodazole, associated with a reduced turnover of the APC/C substrate cyclin B1. These observations suggest that RNF8 regulates the rate of exit from mitosis and cytokinesis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Regulation of mitotic exit by the RNF8 ubiquitin ligase

2007

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“…A number of RING E3 ligase proteins have been found to bind Ubc13 in two-hybrid experiments (18). Screening those candidates revealed that one, Rnf8, was required for Rap80, Abraxas, and Brca1 foci formation in response to DNA damage.…”

Section: Discussionmentioning

confidence: 99%

Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage

Wang

Elledge

2007

Proc. Natl. Acad. Sci. U.S.A.

397

452

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The Brca1 A complex contains Brca1/Bard1, Abraxas, Rap80, and Brcc36; however, with the exception of the Brca1-Abraxas interaction, how the A complex is assembled is not known. The A complex is localized to sites of DNA damage through the UIM domains of RAP80, which bind K63-linked polyubiquitin chains. In this study, we identified an FHA domain RING finger E3 ubiquitin ligase, RNF8, and an E2-conjugating enzyme known to form K63-polyubiquitin chains, Ubc13, each of which is required to recruit the Brca1 A complex to sites of DNA damage. Rnf8 localizes to sites of DNA damage through an FHA-domain-containing region. We found that Rap80 contains an Abraxas interaction domain [AIR (Abraxas-interacting region)], required for association of Rap80 with Abraxas, Brca1, and Brcc36. Abraxas and Brcc36 associate through coiled-coil domains on each protein. These data suggest a model through which Ubc13 and Rnf8 are recruited to sites of DNA damage through DNA-damage-induced phosphorylation of a chromatin-associated protein and generate polyubiquitin chains that then recruit Rap80 and the entire Brca1 A complex to DNA-damage foci. This sequential E3 ubiquitin ligase recruitment constitutes a ubiquitin ligase cascade required for DNA repair and checkpoint signaling.T he Brca1 tumor suppressor is associated with hereditary breast and ovarian cancer and plays critical roles in DNA repair, cell cycle checkpoint control, and maintenance of genomic stability (1, 2). Brca1 contains two C-terminal BRCT repeats and a N-terminal RING domain. Bard1 forms a heterodimeric complex with Brca1 that exhibits E3 ubiquitin ligase activity (3-6). The Brca1 BRCT repeats constitutes a phosphopeptide-recognition domain that binds peptides containing a pSxxF motif (7-9). We and others have found that Brca1 forms at least three distinct complexes (the Brca1 A, B, and C complexes) by binding different adaptor proteins through their pSPxF motifs (10-12). The adaptor proteins are Abraxas (Abra1) for the A complex, Bach1/Brip1 for the B complex, and CTIP for the C complex, and each complex forms in a mutually exclusive manner, which is consistent with the fact that they occupy the same physical location on Brca1. In addition to Abraxas, the Brca1 A complex contains Rap80. A deubiquitinating enzyme, Brcc36, has been shown to be present in the Rap80 and Brca1 complex (11, 13). Thus, Brcc36 is also likely to be part of the Brca1 A complex. How Rap80, Abraxas, and Brcc36 assemble into the Brca1 A complex has not been resolved.Rap80 contains two UIM domains that have been shown to bind K63-linked ubiquitin chains (11). The UIM domains of Rap80 are required for the localization of Rap80 and Abraxas to IR-induced foci (IRIFs) (10,11,14,15). The fact that the UIMs of Rap80 bind to K63-linked polyubiquitin chains implies the existence of an upstream E3 ubiquitin ligase that should play a critical role in the DNA-damage response. An E2 ubiquitinconjugating enzyme, Ubc13, has been implicated previously in Brca1 foci formation (16). Ubc13 forms a complex with an ...

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“…RNF8 interacts with Ubc13 and can catalyze Lys-63-linked ubiquitination of H2A and H2AX at DSB sites (30). RNF8 can also interact with other E2s, including UbcH8 and UbcH5C, for mediating the DNA damage response (31)(32)(33)(34)(35).…”

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confidence: 99%

The RING Finger Protein RNF8 Ubiquitinates Nbs1 to Promote DNA Double-strand Break Repair by Homologous Recombination

Truong

Aslanian

et al. 2012

Journal of Biological Chemistry

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Background:The Mre11-Rad50-Nbs1 (MRN) complex and the ubiquitin E3 ligase RNF8 play important roles in DNA DSB repair. Results: RNF8 interacts with and ubiquitinates Nbs1 to promote binding of Nbs1 to DSBs and HR-mediated DSB repair. Conclusion: Nbs1 ubiquitination by RNF8 is important for Nbs1 recruitment to DSBs and HR-mediated repair of DSBs. Significance: These studies help to understand how ubiquitination modifications contribute to DSB repair and genome stability maintenance in mammalian cells.

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The RING finger protein RNF8 recruits UBC13 for lysine 63‐based self polyubiquitylation

Cited by 91 publications

References 50 publications

Regulation of mitotic exit by the RNF8 ubiquitin ligase

Regulation of mitotic exit by the RNF8 ubiquitin ligase

Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage

The RING Finger Protein RNF8 Ubiquitinates Nbs1 to Promote DNA Double-strand Break Repair by Homologous Recombination

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