Multiple start codons and phosphorylation result in discrete Rad52 protein species

Mayolo, Adriana Antúnez de; Lisby, Michael; Erdeniz, Naz; Thybo, Tanja; Mortensen, Uffe Hasbro; Rothstein, Rodney

doi:10.1093/nar/gkl280

Cited by 33 publications

(27 citation statements)

References 52 publications

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“… PTM: Post-translational modification PO 4 : Phosphorylation UBI: Ubiquitylation SUMO: Sumoylation 1 These residues refer to the revised start codon of RAD52 at methionine 33 (40) as denoted in reference (125), which correspond to residues 43, 44, 210 in reference (149). …”

Section: Figurementioning

confidence: 99%

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Regulation of Homologous Recombination in Eukaryotes

2010

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Homologous recombination is required for accurate chromosome segregation during the first meiotic division and constitutes a key repair and tolerance pathway for complex DNA damage including DNA double-stranded breaks, interstrand crosslinks, and DNA gaps. In addition, recombination and replication are inextricably linked, as recombination recovers stalled and broken replication forks enabling the evolution of larger genomes/replicons. Defects in recombination lead to genomic instability and elevated cancer predisposition, demonstrating a clear cellular need for active recombination. However, recombination can also lead to genome rearrangements. Unrestrained recombination causes undesired endpoints (translocation, deletion, inversion) and the accumulation of toxic recombination intermediates. Evidently, homologous recombination must be carefully regulated to match specific cellular needs. Here we review the mechanistic stages and proteins in recombination that are subject to regulation and suggest that recombination achieves flexibility and robustness by proceeding through meta-stable, reversible intermediates.

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Section: Figurementioning

confidence: 99%

“… 1 These residues refer to the revised start codon of RAD52 at methionine 33 (40) as denoted in reference (125), which correspond to residues 43, 44, 210 in reference (149). …”

Section: Figurementioning

confidence: 99%

Regulation of Homologous Recombination in Eukaryotes

2010

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“…The relevance of these SUMO modifications in regulating HR remains mostly unclear, but in some instances it has been possible to demonstrate a direct role of SUMOylation in regulating protein–protein interactions, protein localization or activity [41]. In particular, SUMOylation of Rad52 at lysines 43, 44 and 253 (using the original amino acid numbering [48] or lysines 10, 11 and 220 when considering the first actual start codon [49]) is induced by DNA damage and shields the protein from proteasomal degradation [44], inhibits its DNA binding and strand annealing activities [50], and inhibits Rad52-mediated recombination within the nucleolus [51]. Important for our understanding of these effects, SUMOylated proteins can be recognized and bound non-covalently by other proteins through a SUMO-interacting motif (SIM) as reported for Srs2 and SUMOylated PCNA, and for Rad51 and SUMOylated Rad52 [46,52–54].…”

Section: Introductionmentioning

confidence: 99%

SUMOylation of Rad52-Rad59 synergistically change the outcome of mitotic recombination

et al. 2016

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Homologous recombination (HR) is essential for maintenance of genome stability through double-strand break (DSB) repair, but at the same time HR can lead to loss of heterozygosity and uncontrolled recombination can be genotoxic. The post-translational modification by SUMO (small ubiquitin-like modifier) has been shown to modulate recombination, but the exact mechanism of this regulation remains unclear. Here we show that SUMOylation stabilizes the interaction between the recombination mediator Rad52 and its paralogue Rad59 in Saccharomyces cerevisiae. Although Rad59 SUMOylation is not required for survival after genotoxic stress, it affects the outcome of recombination to promote conservative DNA repair. In some genetic assays, Rad52 and Rad59 SUMOylation act synergistically. Collectively, our data indicate that the described SUMO modifications affect the balance between conservative and non-conservative mechanisms of HR.

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“…Rad52 is constitutively phosphorylated throughout the cell cycle on some serine and/or threonine residues and additional phosphorylations are induced specifically in S phase [10]. The phosphorylated residues have not yet been identified.…”

Section: Introductionmentioning

confidence: 99%

Rad52 Sumoylation Prevents the Toxicity of Unproductive Rad51 Filaments Independently of the Anti-Recombinase Srs2

Esta

Dupaigne

et al. 2013

PLoS Genet

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The budding yeast Srs2 is the archetype of helicases that regulate several aspects of homologous recombination (HR) to maintain genomic stability. Srs2 inhibits HR at replication forks and prevents high frequencies of crossing-over. Additionally, sensitivity to DNA damage and synthetic lethality with replication and recombination mutants are phenotypes that can only be attributed to another role of Srs2: the elimination of lethal intermediates formed by recombination proteins. To shed light on these intermediates, we searched for mutations that bypass the requirement of Srs2 in DNA repair without affecting HR. Remarkably, we isolated rad52-L264P, a novel allele of RAD52, a gene that encodes one of the most central recombination proteins in yeast. This mutation suppresses a broad spectrum of srs2Δ phenotypes in haploid cells, such as UV and γ-ray sensitivities as well as synthetic lethality with replication and recombination mutants, while it does not significantly affect Rad52 functions in HR and DNA repair. Extensive analysis of the genetic interactions between rad52-L264P and srs2Δ shows that rad52-L264P bypasses the requirement for Srs2 specifically for the prevention of toxic Rad51 filaments. Conversely, this Rad52 mutant cannot restore viability of srs2Δ cells that accumulate intertwined recombination intermediates which are normally processed by Srs2 post-synaptic functions. The avoidance of toxic Rad51 filaments by Rad52-L264P can be explained by a modification of its Rad51 filament mediator activity, as indicated by Chromatin immunoprecipitation and biochemical analysis. Remarkably, sensitivity to DNA damage of srs2Δ cells can also be overcome by stimulating Rad52 sumoylation through overexpression of the sumo-ligase SIZ2, or by replacing Rad52 by a Rad52-SUMO fusion protein. We propose that, like the rad52-L264P mutation, sumoylation modifies Rad52 activity thereby changing the properties of Rad51 filaments. This conclusion is strengthened by the finding that Rad52 is often associated with complete Rad51 filaments in vitro.

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Multiple start codons and phosphorylation result in discrete Rad52 protein species

Cited by 33 publications

References 52 publications

Regulation of Homologous Recombination in Eukaryotes

Regulation of Homologous Recombination in Eukaryotes

SUMOylation of Rad52-Rad59 synergistically change the outcome of mitotic recombination

Rad52 Sumoylation Prevents the Toxicity of Unproductive Rad51 Filaments Independently of the Anti-Recombinase Srs2

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