Regulation of Rad51 function by phosphorylation

Flott, Sonja; Kwon, Youngho; Pigli, Ying Z.; Rice, Phoebe A.; Sung, Patrick; Jackson, Stephen

doi:10.1038/embor.2011.127

Cited by 55 publications

(71 citation statements)

References 22 publications

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“…In Figure 5, we propose a model in which RAD51 loading may attenuate ATR signaling and thereby allow DMC1 loading. However, it is still not known whether ATR regulates DMC1 directly by limiting its ATPase and ssDNA binding activity by phosphorylation, as recently proposed for yeast Rad51 by Mec1 (Flott et al, 2011). The highly conserved motif for ATM/ATR-dependent phosphorylation is also present in Arabidopsis RAD51 and DMC1.…”

Section: Discussionmentioning

confidence: 96%

The Recombinases DMC1 and RAD51 Are Functionally and Spatially Separated during Meiosis in Arabidopsis

et al. 2012

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Meiosis ensures the reduction of the genome before the formation of generative cells and promotes the exchange of genetic information between homologous chromosomes by recombination. Essential for these events are programmed DNA double strand breaks (DSBs) providing single-stranded DNA overhangs after their processing. These overhangs, together with the RADiation sensitive51 (RAD51) and DMC1 Disrupted Meiotic cDNA1 (DMC1) recombinases, mediate the search for homologous sequences. Current models propose that the two ends flanking a meiotic DSB have different fates during DNA repair, but the molecular details remained elusive. Here we present evidence, obtained in the model plant Arabidopsis thaliana, that the two recombinases, RAD51 and DMC1, localize to opposite sides of a meiotic DSB. We further demonstrate that the ATR kinase is involved in regulating DMC1 deposition at meiotic DSB sites, and that its elimination allows DMC1-mediated meiotic DSB repair even in the absence of RAD51. DMC1's ability to promote interhomolog DSB repair is not a property of the protein itself but the consequence of an ASYNAPTIC1 (Hop1)-mediated impediment for intersister repair. Taken together, these results demonstrate that DMC1 functions independently and spatially separated from RAD51 during meiosis and that ATR is an integral part of the regular meiotic program.

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Section: Discussionmentioning

confidence: 96%

The Recombinases DMC1 and RAD51 Are Functionally and Spatially Separated during Meiosis in Arabidopsis

et al. 2012

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“…This reveals a new regulatory mechanism for activating RAD51. Post-translational modification (PTM) of RAD51 is important for its function in DNA repair and tumor radiosensitivity (Flott et al 2011;Krejci et al 2012). For example, Chk1-mediated phosphorylation of RAD51 has been shown to be important for efficient HR (Sorensen et al 2005), while Mec1-mediated phosphorylation of RAD51 is required for its ATPase and DNA-binding activities (Flott et al 2011).…”

Section: The Role Of Uchl3 In Response To Parp Inhibition and Irradiamentioning

confidence: 99%

“…Post-translational modification (PTM) of RAD51 is important for its function in DNA repair and tumor radiosensitivity (Flott et al 2011;Krejci et al 2012). For example, Chk1-mediated phosphorylation of RAD51 has been shown to be important for efficient HR (Sorensen et al 2005), while Mec1-mediated phosphorylation of RAD51 is required for its ATPase and DNA-binding activities (Flott et al 2011). Phosphorylation of Tyr315 by BCR/ ABL is important for DSB repair and drug resistance, while phosphorylation of Tyr54 by c-Abl inhibits RAD51 binding to DNA and its ATP-dependent DNA strand exchange reaction (Yuan et al 1998;Slupianek et al 2011).…”

Section: The Role Of Uchl3 In Response To Parp Inhibition and Irradiamentioning

confidence: 99%

A phosphorylation–deubiquitination cascade regulates the BRCA2–RAD51 axis in homologous recombination

Luo

et al. 2016

Genes Dev.

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Homologous recombination (HR) is one of the major DNA double-strand break (DSB) repair pathways in mammalian cells. Defects in HR trigger genomic instability and result in cancer predisposition. The defining step of HR is homologous strand exchange directed by the protein RAD51, which is recruited to DSBs by BRCA2. However, the regulation of the BRCA2-RAD51 axis remains unclear. Here we report that ubiquitination of RAD51 hinders RAD51-BRCA2 interaction, while deubiquitination of RAD51 facilitates RAD51-BRCA2 binding and RAD51 recruitment and thus is critical for proper HR. Mechanistically, in response to DNA damage, the deubiquitinase UCHL3 is phosphorylated and activated by ATM. UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2. Overexpression of UCHL3 renders breast cancer cells resistant to radiation and chemotherapy, while depletion of UCHL3 sensitizes cells to these treatments, suggesting a determinant role of UCHL3 in cancer therapy. Overall, we identify UCHL3 as a novel regulator of DNA repair and reveal a model in which a phosphorylation-deubiquitination cascade dynamically regulates the BRCA2-RAD51 pathway.

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“…For example, the activity of Rad51, the yeast RecA homologue involved in DSB repair through homologous recombination, is regulated by phoshorylation. Both Rad51 and eukaryotic single strand-binding protein (SSB) are phosphorylated by DNA damage-responsive protein kinases (14,15). Rad51 phosphorylation by Mec1, an ATR homologue in Saccharomyces cerevisiae, regulates its functions in vitro and in vivo.…”

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confidence: 99%

Phosphorylation of Deinococcus radiodurans RecA Regulates Its Activity and May Contribute to Radioresistance

Rajpurohit

Bihani

Waldor

et al. 2016

Journal of Biological Chemistry

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Deinococcus radiodurans has a remarkable capacity to survive exposure to extreme levels of radiation that cause hundreds of DNA double strand breaks (DSBs). DSB repair in this bacterium depends on its recombinase A protein (DrRecA). DrRecA plays a pivotal role in both extended synthesis-dependent strand annealing and slow crossover events of DSB repair during the organism's recovery from DNA damage. The mechanisms that control DrRecA activity during the D. radiodurans response to ␥ radiation exposure are unknown. Here, we show that DrRecA undergoes phosphorylation at Tyr-77 and Thr-318 by a DNA damage-responsive serine threonine/tyrosine protein kinase (RqkA). Phosphorylation modifies the activity of DrRecA in several ways, including increasing its affinity for dsDNA and its preference for dATP over ATP. Strand exchange reactions catalyzed by phosphorylated versus unphosphorylated DrRecA also differ. In silico analysis of DrRecA structure support the idea that phosphorylation can modulate crucial functions of this protein. Collectively, our findings suggest that phosphorylation of DrRecA enables the recombinase to selectively use abundant dsDNA substrate present during post-irradiation recovery for efficient DSB repair, thereby promoting the extraordinary radioresistance of D. radiodurans.Deinococcus radiodurans has a remarkable capacity to survive extreme doses of radiations and other DNA-damaging agents. Studies aimed at unraveling the molecular bases for these unusual properties have revealed that D. radiodurans encodes mechanisms for highly efficient DNA double strand break (DSB) 2 repair and oxidative stress management (1-3). DSB repair in this Gram-positive bacterium is accomplished in two phases during post-irradiation recovery (PIR); phase I is dominated by extended synthesis-dependent strand annealing (ESDSA) processes, whereas phase II involves slow crossover events in homologous recombination leading to the repair and re-establishment of the multipartite D. radiodurans genome structure (4). Despite the fact that the two phases of PIR have DNA substrates of different structures and topologies, D. radiodurans RecA (DrRecA) is required throughout DSB repair during PIR (5). Biochemical characterization of recombinant DrRecA revealed that it can form a filament on singlestranded DNA (ssDNA), exhibit co-protease activity, and utilize ATP or dATP for its energy requirements, akin to other bacterial RecA proteins (6), but it also has unusual properties. In contrast to most bacterial RecA proteins, DrRecA promotes inverse strand exchange reactions (7). Also, DrRecA promotes DNA degradation during the early phase of ESDSA repair (5), which is opposite to the function observed with Escherichia coli RecA. Transcription of DrRecA is induced in response to ␥ radiation (8, 9). However, the mechanisms by which ␥ radiation induces DrRecA expression are unusual. Inactivation of both D. radiodurans lexA genes does not attenuate ␥ radiation induction of DrRecA expression (10, 11). Thus, in contrast to many bacteria, LexA...

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Regulation of Rad51 function by phosphorylation

Cited by 55 publications

References 22 publications

The Recombinases DMC1 and RAD51 Are Functionally and Spatially Separated during Meiosis in Arabidopsis

The Recombinases DMC1 and RAD51 Are Functionally and Spatially Separated during Meiosis in Arabidopsis

A phosphorylation–deubiquitination cascade regulates the BRCA2–RAD51 axis in homologous recombination

Phosphorylation of Deinococcus radiodurans RecA Regulates Its Activity and May Contribute to Radioresistance

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