Dataset Information

RAP80, ubiquitin and SUMO in the DNA damage response.

ABSTRACT: A decade has passed since the first reported connection between RAP80 and BRCA1 in DNA double-strand break repair. Despite the initial identification of RAP80 as a factor localizing BRCA1 to DNA double-strand breaks and potentially promoting homologous recombination, there is increasing evidence that RAP80 instead suppresses homologous recombination to fine-tune the balance of competing DNA repair processes during the S/G2 phase of the cell cycle. RAP80 opposes homologous recombination by inhibiting DNA end-resection and sequestering BRCA1 into the BRCA1-A complex. Ubiquitin and SUMO modifications of chromatin at DNA double-strand breaks recruit RAP80, which contains distinct sequence motifs that recognize ubiquitin and SUMO. Here, we review RAP80's role in repressing homologous recombination at DNA double-strand breaks and how this role is facilitated by its ability to bind ubiquitin and SUMO modifications.

SUBMITTER: Lombardi PM

PROVIDER: S-EPMC5570449 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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RAP80, ubiquitin and SUMO in the DNA damage response.

Lombardi Patrick M PM Matunis Michael J MJ Wolberger Cynthia C

Journal of molecular medicine (Berlin, Germany) 20170705 8

A decade has passed since the first reported connection between RAP80 and BRCA1 in DNA double-strand break repair. Despite the initial identification of RAP80 as a factor localizing BRCA1 to DNA double-strand breaks and potentially promoting homologous recombination, there is increasing evidence that RAP80 instead suppresses homologous recombination to fine-tune the balance of competing DNA repair processes during the S/G<sub>2</sub> phase of the cell cycle. RAP80 opposes homologous recombinatio ...[more]

PMID: 28681078

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Project description:In eukaryotes many players in the DNA-damage response (DDR) catalyze protein sumoylation or ubiquitylation. Emphasis has been placed on how these modifications orchestrate the sequential recruitment of repair factors to sites of DNA damage or stalled replication forks. Here, we shed light on a pathway in which sumoylated factors are eliminated through the coupled action of Sumo-targeted ubiquitin ligases (STUbLs) and the ubiquitin-fusion degradation protein 1 (Ufd1). Ufd1 is a subunit of the Cdc48-Ufd1-Npl4 complex implicated in the sorting of ubiquitylated substrates for degradation by the proteasome. We find that in fission yeast, Ufd1 interacts physically and functionally with the Sumo-targeted ubiquitin ligase (STUbL) Rfp1, homologous to human RNF4, and with the Sumo E3 ligase Pli1, homologous to human PIAS1. Deleting a C-terminal domain of Ufd1 that mediates the interaction of Ufd1 with Rfp1, Pli1, and Sumo (ufd1?Ct(213-342) ) lead to an accumulation of high-molecular-weight Sumo conjugates and caused severe genomic instabilities. The spectrum of sensitivity of ufd1?Ct(213-342) cells to genotoxins, the epistatic relationships of ufd1?Ct(213-342) with mutations in DNA repair factors, and the localization of the repair factor Rad22 in ufd1?Ct(213-342) cells point to ufd1?Ct(213-342) cells accumulating aberrant structures during replication that require homologous recombination (HR) for their repair. We present evidence that HR is however often not successful in ufd1?Ct(213-342) cells and we identify Rad22 as one of the high-molecular-weight conjugates accumulating in the ufd1?Ct(213-342) mutant consistent with Rad22 being a STUbL/Ufd1 substrate. Suggesting a direct role of Ufd1 in the processing of Sumo-conjugates, Ufd1 formed nuclear foci colocalizing with Sumo during the DDR, and Sumo-conjugates accumulated in foci in the ufd1?Ct(213-342) mutant. Broader functional relationships between Ufd1 and STUbLs conceivably affect numerous cellular processes beyond the DDR.

Dataset Information

RAP80, ubiquitin and SUMO in the DNA damage response.

Publications

RAP80, ubiquitin and SUMO in the DNA damage response.

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