Статті в журналах: "Rad51 filament"

1

Ma, Emilie, Laurent Maloisel, Léa Le Falher, Raphaël Guérois, and Eric Coïc. "Rad52 Oligomeric N-Terminal Domain Stabilizes Rad51 Nucleoprotein Filaments and Contributes to Their Protection against Srs2." Cells 10, no. 6 (June 11, 2021): 1467. http://dx.doi.org/10.3390/cells10061467.

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Homologous recombination (HR) depends on the formation of a nucleoprotein filament of the recombinase Rad51 to scan the genome and invade the homologous sequence used as a template for DNA repair synthesis. Therefore, HR is highly accurate and crucial for genome stability. Rad51 filament formation is controlled by positive and negative factors. In Saccharomyces cerevisiae, the mediator protein Rad52 catalyzes Rad51 filament formation and stabilizes them, mostly by counteracting the disruptive activity of the translocase Srs2. Srs2 activity is essential to avoid the formation of toxic Rad51 filaments, as revealed by Srs2-deficient cells. We previously reported that Rad52 SUMOylation or mutations disrupting the Rad52–Rad51 interaction suppress Rad51 filament toxicity because they disengage Rad52 from Rad51 filaments and reduce their stability. Here, we found that mutations in Rad52 N-terminal domain also suppress the DNA damage sensitivity of Srs2-deficient cells. Structural studies showed that these mutations affect the Rad52 oligomeric ring structure. Overall, in vivo and in vitro analyzes of these mutants indicate that Rad52 ring structure is important for protecting Rad51 filaments from Srs2, but can increase Rad51 filament stability and toxicity in Srs2-deficient cells. This stabilization function is distinct from Rad52 mediator and annealing activities.

2

Maloisel, Laurent, Emilie Ma, Jamie Phipps, Alice Deshayes, Stefano Mattarocci, Stéphane Marcand, Karine Dubrana, and Eric Coïc. "Rad51 filaments assembled in the absence of the complex formed by the Rad51 paralogs Rad55 and Rad57 are outcompeted by translesion DNA polymerases on UV-induced ssDNA gaps." PLOS Genetics 19, no. 2 (February 7, 2023): e1010639. http://dx.doi.org/10.1371/journal.pgen.1010639.

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The bypass of DNA lesions that block replicative polymerases during DNA replication relies on DNA damage tolerance pathways. The error-prone translesion synthesis (TLS) pathway depends on specialized DNA polymerases that incorporate nucleotides in front of base lesions, potentially inducing mutagenesis. Two error-free pathways can bypass the lesions: the template switching pathway, which uses the sister chromatid as a template, and the homologous recombination pathway (HR), which also can use the homologous chromosome as template. The balance between error-prone and error-free pathways controls the mutagenesis level. Therefore, it is crucial to precisely characterize factors that influence the pathway choice to better understand genetic stability at replication forks. In yeast, the complex formed by the Rad51 paralogs Rad55 and Rad57 promotes HR and template-switching at stalled replication forks. At DNA double-strand breaks (DSBs), this complex promotes Rad51 filament formation and stability, notably by counteracting the Srs2 anti-recombinase. To explore the role of the Rad55-Rad57 complex in error-free pathways, we monitored the genetic interactions between Rad55-Rad57, the translesion polymerases Polζ or Polη, and Srs2 following UV radiation that induces mostly single-strand DNA gaps. We found that the Rad55-Rad57 complex was involved in three ways. First, it protects Rad51 filaments from Srs2, as it does at DSBs. Second, it promotes Rad51 filament stability independently of Srs2. Finally, we observed that UV-induced HR is almost abolished in Rad55-Rad57 deficient cells, and is partially restored upon Polζ or Polη depletion. Hence, we propose that the Rad55-Rad57 complex is essential to promote Rad51 filament stability on single-strand DNA gaps, notably to counteract the error-prone TLS polymerases and mutagenesis.

3

Sullivan, Meghan R., and Kara A. Bernstein. "RAD-ical New Insights into RAD51 Regulation." Genes 9, no. 12 (December 13, 2018): 629. http://dx.doi.org/10.3390/genes9120629.

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The accurate repair of DNA is critical for genome stability and cancer prevention. DNA double-strand breaks are one of the most toxic lesions; however, they can be repaired using homologous recombination. Homologous recombination is a high-fidelity DNA repair pathway that uses a homologous template for repair. One central HR step is RAD51 nucleoprotein filament formation on the single-stranded DNA ends, which is a step required for the homology search and strand invasion steps of HR. RAD51 filament formation is tightly controlled by many positive and negative regulators, which are collectively termed the RAD51 mediators. The RAD51 mediators function to nucleate, elongate, stabilize, and disassemble RAD51 during repair. In model organisms, RAD51 paralogs are RAD51 mediator proteins that structurally resemble RAD51 and promote its HR activity. New functions for the RAD51 paralogs during replication and in RAD51 filament flexibility have recently been uncovered. Mutations in the human RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3, and SWSAP1) are found in a subset of breast and ovarian cancers. Despite their discovery three decades ago, few advances have been made in understanding the function of the human RAD51 paralogs. Here, we discuss the current perspective on the in vivo and in vitro function of the RAD51 paralogs, and their relationship with cancer in vertebrate models.

4

Burgess, Rebecca C., Michael Lisby, Veronika Altmannova, Lumir Krejci, Patrick Sung, and Rodney Rothstein. "Localization of recombination proteins and Srs2 reveals anti-recombinase function in vivo." Journal of Cell Biology 185, no. 6 (June 8, 2009): 969–81. http://dx.doi.org/10.1083/jcb.200810055.

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Homologous recombination (HR), although an important DNA repair mechanism, is dangerous to the cell if improperly regulated. The Srs2 “anti-recombinase” restricts HR by disassembling the Rad51 nucleoprotein filament, an intermediate preceding the exchange of homologous DNA strands. Here, we cytologically characterize Srs2 function in vivo and describe a novel mechanism for regulating the initiation of HR. We find that Srs2 is recruited separately to replication and repair centers and identify the genetic requirements for recruitment. In the absence of Srs2 activity, Rad51 foci accumulate, and surprisingly, can form in the absence of Rad52 mediation. However, these Rad51 foci do not represent repair-proficient filaments, as determined by recombination assays. Antagonistic roles for Rad52 and Srs2 in Rad51 filament formation are also observed in vitro. Furthermore, we provide evidence that Srs2 removes Rad51 indiscriminately from DNA, while the Rad52 protein coordinates appropriate filament reformation. This constant breakdown and rebuilding of filaments may act as a stringent quality control mechanism during HR.

5

Liu, Jie, Ludovic Renault, Xavier Veaute, Francis Fabre, Henning Stahlberg, and Wolf-Dietrich Heyer. "Rad51 paralogues Rad55–Rad57 balance the antirecombinase Srs2 in Rad51 filament formation." Nature 479, no. 7372 (October 23, 2011): 245–48. http://dx.doi.org/10.1038/nature10522.

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6

Osman, Fekret, Julie Dixon, Alexis R. Barr, and Matthew C. Whitby. "The F-Box DNA Helicase Fbh1 Prevents Rhp51-Dependent Recombination without Mediator Proteins." Molecular and Cellular Biology 25, no. 18 (September 15, 2005): 8084–96. http://dx.doi.org/10.1128/mcb.25.18.8084-8096.2005.

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ABSTRACT A key step in homologous recombination is the loading of Rad51 onto single-stranded DNA to form a nucleoprotein filament that promotes homologous DNA pairing and strand exchange. Mediator proteins, such as Rad52 and Rad55-Rad57, are thought to aid filament assembly by overcoming an inhibitory effect of the single-stranded-DNA-binding protein replication protein A. Here we show that mediator proteins are also required to enable fission yeast Rad51 (called Rhp51) to function in the presence of the F-box DNA helicase Fbh1. In particular, we show that the critical function of Rad22 (an orthologue of Rad52) in promoting Rhp51-dependent recombination and DNA repair can be mostly circumvented by deleting fbh1. Similarly, the reduced growth/viability and DNA damage sensitivity of an fbh1 − mutant are variously suppressed by deletion of any one of the mediators Rad22, Rhp55, and Swi5. From these data we propose that Rhp51 action is controlled through an interplay between Fbh1 and the mediator proteins. Colocalization of Fbh1 with Rhp51 damage-induced foci suggests that this interplay occurs at the sites of nucleoprotein filament assembly. Furthermore, analysis of different fbh1 mutant alleles suggests that both the F-box and helicase activities of Fbh1 contribute to controlling Rhp51.

7

Fung, Cindy W., Gary S. Fortin, Shaun E. Peterson, and Lorraine S. Symington. "The rad51-K191R ATPase-Defective Mutant Is Impaired forPresynaptic Filament Formation." Molecular and Cellular Biology 26, no. 24 (October 9, 2006): 9544–54. http://dx.doi.org/10.1128/mcb.00599-06.

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ABSTRACT The nucleoprotein filament formed by Rad51 polymerization on single-stranded DNA is essential for homologous pairing and strand exchange. ATP binding is required for Rad51 nucleoprotein filament formation and strand exchange, but ATP hydrolysis is not required for these functions in vitro. Previous studies have shown that a yeast strain expressing the rad51-K191R allele is sensitive to ionizing radiation, suggesting an important role for ATP hydrolysis in vivo. The recruitment of Rad51-K191R to double-strand breaks is defective in vivo, and this phenotype can be suppressed by elimination of the Srs2 helicase, an antagonist of Rad51 filament formation. The phenotype of the rad51-K191R strain is also suppressed by overexpression of Rad54. In vitro, the Rad51-K191R protein exhibits a slight decrease in binding to DNA, consistent with the defect in presynaptic filament formation. However, the rad51-K191R mutation is dominant in heterozygous diploids, indicating that the defect is not due simply to reduced affinity for DNA. We suggest the Rad51-K191R protein either forms an altered filament or is defective in turnover, resulting in a reduced pool of free protein available for DNA binding.

8

Lu, Chih-Hao, Hsin-Yi Yeh, Guan-Chin Su, Kentaro Ito, Yumiko Kurokawa, Hiroshi Iwasaki, Peter Chi, and Hung-Wen Li. "Swi5–Sfr1 stimulates Rad51 recombinase filament assembly by modulating Rad51 dissociation." Proceedings of the National Academy of Sciences 115, no. 43 (October 8, 2018): E10059—E10068. http://dx.doi.org/10.1073/pnas.1812753115.

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Eukaryotic Rad51 protein is essential for homologous-recombination repair of DNA double-strand breaks. Rad51 recombinases first assemble onto single-stranded DNA to form a nucleoprotein filament, required for function in homology pairing and strand exchange. This filament assembly is the first regulation step in homologous recombination. Rad51 nucleation is kinetically slow, and several accessory factors have been identified to regulate this step. Swi5–Sfr1 (S5S1) stimulates Rad51-mediated homologous recombination by stabilizing Rad51 nucleoprotein filaments, but the mechanism of stabilization is unclear. We used single-molecule tethered particle motion experiments to show that mouse S5S1 (mS5S1) efficiently stimulates mouse RAD51 (mRAD51) nucleus formation and inhibits mRAD51 dissociation from filaments. We also used single-molecule fluorescence resonance energy transfer experiments to show that mS5S1 promotes stable nucleus formation by specifically preventing mRAD51 dissociation. This leads to a reduction of nucleation size from three mRAD51 to two mRAD51 molecules in the presence of mS5S1. Compared with mRAD51, fission yeast Rad51 (SpRad51) exhibits fast nucleation but quickly dissociates from the filament. SpS5S1 specifically reduces SpRad51 disassembly to maintain a stable filament. These results clearly demonstrate the conserved function of S5S1 by primarily stabilizing Rad51 on DNA, allowing both the formation of the stable nucleus and the maintenance of filament length.

9

Muhammad, Ali Akbar, Clara Basto, Thibaut Peterlini, Josée Guirouilh-Barbat, Melissa Thomas, Xavier Veaute, Didier Busso, et al. "Human RAD52 stimulates the RAD51-mediated homology search." Life Science Alliance 7, no. 3 (December 11, 2023): e202201751. http://dx.doi.org/10.26508/lsa.202201751.

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Homologous recombination (HR) is a DNA repair mechanism of double-strand breaks and blocked replication forks, involving a process of homology search leading to the formation of synaptic intermediates that are regulated to ensure genome integrity. RAD51 recombinase plays a central role in this mechanism, supported by its RAD52 and BRCA2 partners. If the mediator function of BRCA2 to load RAD51 on RPA-ssDNA is well established, the role of RAD52 in HR is still far from understood. We used transmission electron microscopy combined with biochemistry to characterize the sequential participation of RPA, RAD52, and BRCA2 in the assembly of the RAD51 filament and its activity. Although our results confirm that RAD52 lacks a mediator activity, RAD52 can tightly bind to RPA-coated ssDNA, inhibit the mediator activity of BRCA2, and form shorter RAD51-RAD52 mixed filaments that are more efficient in the formation of synaptic complexes and D-loops, resulting in more frequent multi-invasions as well. We confirm the in situ interaction between RAD51 and RAD52 after double-strand break induction in vivo. This study provides new molecular insights into the formation and regulation of presynaptic and synaptic intermediates by BRCA2 and RAD52 during human HR.

10

Slupianek, Artur, Shuyue Ren, and Tomasz Skorski. "Selective Anti-Leukemia Targeting of the Interaction Between BCR/ABL and Mammalian RecA Homologs." Blood 112, no. 11 (November 16, 2008): 195. http://dx.doi.org/10.1182/blood.v112.11.195.195.

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Abstract We showed before that cells transformed by BCR/ABL and other fusion tyrosine kinases (FTKs) such as TEL/ABL, TEL/JAK2 and TEL/PDGFR, inducing chronic myeloproliferative disorders (MPDs), and CD34+ chronic myeloid leukemia (CML) stem/ progenitor cells from chronic phase (CML-CP) and blast crisis (CML-BC) contain an excess of DNA double-strand breaks (DSBs) induced by reactive oxygen species (ROS) and genotoxic stress [Blood, 2005; Cell Cycle, 2006; DNA Repair, 2006; Cancer Res., 2008]. Recent studies also revealed that CD34+CD38− CML-CP and CML-BC stem cellenriched populations seem to display more DSBs than normal counterparts as measured by gamma-H2AX foci formation on DNA. Elevated levels of DSBs were also observed in leukemia cells expressing imatinib-resistant BCR/ABL kinase mutants. DSBs may cause apoptosis if not repaired or chromosomal aberrations if repaired unfaithfully. Numerous ROS- and radiation- induced DSBs are not lethal for BCR/ABL-positive leukemia cells; instead, they induce chromosomal instability implicating enhanced, but unfaithful repair [Leukemia, 2008]. The previous report [Mol. Cell, 2001] and ongoing studies demonstrated that BCR/ABL kinase (non-mutated and imatinib-resistant mutants) modulates expression of the mammalian RecA homologs RAD51, RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3, which are responsible for homologous recombination repair (HRR) of DSBs. RAD51 plays a key role in HRR in cells transformed by BCR/ ABL and other FTKs [Mol. Cell, 2001; Mol. Cell. Biol., 2002]. BCR/ABL stimulates the expression of, interacts with and phosphorylates RAD51 on Y315, which is located in a critical fragment of RAD51 essential for its filament formation on DNA. Accordingly, our recent results indicated that BCR/ABL-mediated RAD51[Y315] phosphorylation appears to be important for nuclear RAD51 foci formation in response to DNA damage. In addition to RAD51, BCR/ABL interacts directly with and phosphorylates RAD51B and XRCC2, but not other RecA homologs. Altogether, it appears that BCR/ABL can deregulate the expression and phosphorylation of some RecA homologs, which may have a significant impact on the efficiency and fidelity of DSB repair resulting in protection from apoptosis and chromosomal instability. Therefore, disassembly of BCR/ABL from RecA homologs should reduce the capability of CML cells to repair numerous ROS-induced DSBs and eventually trigger apoptosis. Based on this hypothesis we investigated the mechanisms of association between BCR/ABL and RecA homologs. Interactions between BCR/ ABL and RAD51 or RAD51B depend on the proline- rich (PP) regions of RAD51 and RAD51B, and the SH3 domain and SH2-catalytic domain (SH2-CD) linker of BCR/ABL, which form a pocket binding the PP regions. Disruption of the PP regions of RAD51 by P-L amino acid substitutions (PP-LL mutants) abrogated direct interaction with the BCR/ABL SH3-SH2-CD pocket. On the other hand, single amino acid substitutions in the BCR/ABL SH3-SH2-CD pocket, which eliminated its capability of binding the PP regions, prevented complex formation with RAD51 and RAD51B. In addition, RAD51 and RAD51B may interact with members of the BCR/ABL proteome such as Grb2 and Shc (RAD51 and RAD51B), and c-CrkL (only RAD51B), but not Gab2 and c-Cbl. 32Dcl3 murine hematopoietic cells expressing BCR/ABL SH3-SH2-CD pocket mutant, where single amino acid substitutions disrupted its direct interaction with RAD51, displayed a slower proliferation rate and responded poorly to genotoxic stress despite intact kinase activity in comparison to cells transformed with non-mutated BCR/ABL. Interestingly, expression of RAD51 PP-LL mutant eliminated BCR/ABL-transformed leukemia cells, without any toxic effect on normal counterparts. These results suggest that the interaction between BCR/ABL and RAD51 may be targeted for selective elimination of leukemia cells and/or suppression of genomic instability. To test this hypothesis we are employing the peptide aptamer strategy targeting RAD51 PP regions in CD34+ cells obtained from imatinib-sensitive and imatinib-resistant CML patients and healthy volunteers in vivo and in vitro. In summary, we hypothesize that mechanisms regulating the association of BCR/ABL with RAD51 and other mammalian RecA homologs may be explored for the planning of more effective anti-tumor modalities.

11

Li, X., X. P. Zhang, J. A. Solinger, K. Kiianitsa, X. Yu, E. H. Egelman, and W. D. Heyer. "Rad51 and Rad54 ATPase activities are both required to modulate Rad51-dsDNA filament dynamics." Nucleic Acids Research 35, no. 12 (June 6, 2007): 4124–40. http://dx.doi.org/10.1093/nar/gkm412.

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12

Subramanyam, Shyamal, Mohammed Ismail, Ipshita Bhattacharya, and Maria Spies. "Tyrosine phosphorylation stimulates activity of human RAD51 recombinase through altered nucleoprotein filament dynamics." Proceedings of the National Academy of Sciences 113, no. 41 (September 26, 2016): E6045—E6054. http://dx.doi.org/10.1073/pnas.1604807113.

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The DNA strand exchange protein RAD51 facilitates the central step in homologous recombination, a process fundamentally important for accurate repair of damaged chromosomes, restart of collapsed replication forks, and telomere maintenance. The active form of RAD51 is a nucleoprotein filament that assembles on single-stranded DNA (ssDNA) at the sites of DNA damage. The c-Abl tyrosine kinase and its oncogenic counterpart BCR-ABL fusion kinase phosphorylate human RAD51 on tyrosine residues 54 and 315. We combined biochemical reconstitutions of the DNA strand exchange reactions with total internal reflection fluorescence microscopy to determine how the two phosphorylation events affect the biochemical activities of human RAD51 and properties of the RAD51 nucleoprotein filament. By mimicking RAD51 tyrosine phosphorylation with a nonnatural amino acid, p-carboxymethyl-l-phenylalanine (pCMF), we demonstrated that Y54 phosphorylation enhances the RAD51 recombinase activity by at least two different mechanisms, modifies the RAD51 nucleoprotein filament formation, and allows RAD51 to compete efficiently with ssDNA binding protein RPA. In contrast, Y315 phosphorylation has little effect on the RAD51 activities. Based on our work and previous cellular studies, we propose a mechanism underlying RAD51 activation by c-Abl/BCR-ABL kinases.

13

Mazina, Olga M., and Alexander V. Mazin. "Human Rad54 Protein Stimulates DNA Strand Exchange Activity of hRad51 Protein in the Presence of Ca2+." Journal of Biological Chemistry 279, no. 50 (October 4, 2004): 52042–51. http://dx.doi.org/10.1074/jbc.m410244200.

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Rad51 and Rad54 proteins play a key role in homologous recombination in eukaryotes. Recently, we reported that Ca2+is requiredin vitrofor human Rad51 protein to form an active nucleoprotein filament that is important for the search of homologous DNA and for DNA strand exchange, two critical steps of homologous recombination. Here we find that Ca2+is also required for hRad54 protein to effectively stimulate DNA strand exchange activity of hRad51 protein. This finding identifies Ca2+as a universal cofactor of DNA strand exchange promoted by mammalian homologous recombination proteinsin vitro. We further investigated the hRad54-dependent stimulation of DNA strand exchange. The mechanism of stimulation appeared to include specific interaction of hRad54 protein with the hRad51 nucleoprotein filament. Our results show that hRad54 protein significantly stimulates homology-independent coaggregation of dsDNA with the filament, which represents an essential step of the search for homologous DNA. The results obtained indicate that hRad54 protein serves as a dsDNA gateway for the hRad51-ssDNA filament, promoting binding and an ATP hydrolysis-dependent translocation of dsDNA during the search for homologous sequences.

14

Zhang, Hongshan, Jeffrey M. Schaub, and Ilya J. Finkelstein. "RADX condenses single-stranded DNA to antagonize RAD51 loading." Nucleic Acids Research 48, no. 14 (July 4, 2020): 7834–43. http://dx.doi.org/10.1093/nar/gkaa559.

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Abstract RADX is a mammalian single-stranded DNA-binding protein that stabilizes telomeres and stalled replication forks. Cellular biology studies have shown that the balance between RADX and Replication Protein A (RPA) is critical for DNA replication integrity. RADX is also a negative regulator of RAD51-mediated homologous recombination at stalled forks. However, the mechanism of RADX acting on DNA and its interactions with RPA and RAD51 are enigmatic. Using single-molecule imaging of the key proteins in vitro, we reveal that RADX condenses ssDNA filaments, even when the ssDNA is coated with RPA at physiological protein ratios. RADX compacts RPA-coated ssDNA filaments via higher-order assemblies that can capture ssDNA in trans. Furthermore, RADX blocks RPA displacement by RAD51 and prevents RAD51 loading on ssDNA. Our results indicate that RADX is an ssDNA condensation protein that inhibits RAD51 filament formation and may antagonize other ssDNA-binding proteins on RPA-coated ssDNA.

15

Kiianitsa, K., J. A. Solinger, and W. D. Heyer. "Terminal association of Rad54 protein with the Rad51-dsDNA filament." Proceedings of the National Academy of Sciences 103, no. 26 (June 19, 2006): 9767–72. http://dx.doi.org/10.1073/pnas.0604240103.

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16

Godin, Stephen K., Meghan R. Sullivan, and Kara A. Bernstein. "Novel insights into RAD51 activity and regulation during homologous recombination and DNA replication." Biochemistry and Cell Biology 94, no. 5 (October 2016): 407–18. http://dx.doi.org/10.1139/bcb-2016-0012.

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In this review we focus on new insights that challenge our understanding of homologous recombination (HR) and Rad51 regulation. Recent advances using high-resolution microscopy and single molecule techniques have broadened our knowledge of Rad51 filament formation and strand invasion at double-strand break (DSB) sites and at replication forks, which are one of most physiologically relevant forms of HR from yeast to humans. Rad51 filament formation and strand invasion is regulated by many mediator proteins such as the Rad51 paralogues and the Shu complex, consisting of a Shu2/SWS1 family member and additional Rad51 paralogues. Importantly, a novel RAD51 paralogue was discovered in Caenorhabditis elegans, and its in vitro characterization has demonstrated a new function for the worm RAD51 paralogues during HR. Conservation of the human RAD51 paralogues function during HR and repair of replicative damage demonstrate how the RAD51 mediators play a critical role in human health and genomic integrity. Together, these new findings provide a framework for understanding RAD51 and its mediators in DNA repair during multiple cellular contexts.

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Conway, Adam B., Thomas W. Lynch, Ying Zhang, Gary S. Fortin, Cindy W. Fung, Lorraine S. Symington, and Phoebe A. Rice. "Crystal structure of a Rad51 filament." Nature Structural & Molecular Biology 11, no. 8 (July 4, 2004): 791–96. http://dx.doi.org/10.1038/nsmb795.

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18

Cash, Kailey, and Maria Spies. "RAD51 filament formation, dynamics, and regulation." Biophysical Journal 122, no. 3 (February 2023): 355a. http://dx.doi.org/10.1016/j.bpj.2022.11.1968.

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19

Herzberg, Kristina, Vladimir I. Bashkirov, Michael Rolfsmeier, Edwin Haghnazari, W. Hayes McDonald, Scott Anderson, Elena V. Bashkirova, John R. Yates, and Wolf-Dietrich Heyer. "Phosphorylation of Rad55 on Serines 2, 8, and 14 Is Required for Efficient Homologous Recombination in the Recovery of Stalled Replication Forks." Molecular and Cellular Biology 26, no. 22 (September 11, 2006): 8396–409. http://dx.doi.org/10.1128/mcb.01317-06.

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ABSTRACT DNA damage checkpoints coordinate the cellular response to genotoxic stress and arrest the cell cycle in response to DNA damage and replication fork stalling. Homologous recombination is a ubiquitous pathway for the repair of DNA double-stranded breaks and other checkpoint-inducing lesions. Moreover, homologous recombination is involved in postreplicative tolerance of DNA damage and the recovery of DNA replication after replication fork stalling. Here, we show that the phosphorylation on serines 2, 8, and 14 (S2,8,14) of the Rad55 protein is specifically required for survival as well as for normal growth under genome-wide genotoxic stress. Rad55 is a Rad51 paralog in Saccharomyces cerevisiae and functions in the assembly of the Rad51 filament, a central intermediate in recombinational DNA repair. Phosphorylation-defective rad55-S2,8,14A mutants display a very slow traversal of S phase under DNA-damaging conditions, which is likely due to the slower recovery of stalled replication forks or the slower repair of replication-associated DNA damage. These results suggest that Rad55-S2,8,14 phosphorylation activates recombinational repair, allowing for faster recovery after genotoxic stress.

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Adolph, Madison, Swati Balakrishnan, Walter Chazin, and David Cortez. "Abstract IA024: Mechanistic insights into how RADX regulates RAD51 nucleoprotein filaments to maintain genome stability and control replication stress responses." Cancer Research 84, no. 1_Supplement (January 9, 2024): IA024. http://dx.doi.org/10.1158/1538-7445.dnarepair24-ia024.

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Abstract RAD51 nucleoprotein filaments are central to maintaining genome stability, governing crucial processes like homology-directed double-strand break repair, replication fork reversal, and shielding replication forks from nucleases. The precise regulation of RAD51 filament formation and stability is critical for these functions, which suppress tumorigenesis and determine cellular responses to common cancer therapies. RADX is a pivotal regulator of RAD51 in the context of DNA replication, impacting replication fork reversal and fork stabilization. After identifying RADX as an RPA-related RAD51 regulator, we have worked to understand how it acts, thereby elucidating its role in genome stability and its influence on cancer cell responses to PARP inhibitors and chemotherapies. Genetically, RADX exhibits a dual role, capable of either inhibiting or promoting replication fork reversal based on the levels of replication stress. Biochemical studies show that RADX has inhibitory effects on RAD51 strand exchange and D-loop formation activities, achieved through direct binding to single-strand DNA and RAD51, along with the stimulation of RAD51 ATP hydrolysis. These activities collectively destabilize RAD51 nucleofilaments, opposing the stabilizing effects of BRCA2. Cells lacking RADX regulatory functions exhibit replication defects, DNA damage accumulation, reduced growth, and heightened sensitivity to DNA damage and replication stress. Structural analyses, including cryo-electron microscopy and mass photometry, revealed how RADX binds ssDNA and show it exists in multiple oligomeric states with a preference for trimers when bound to single-stranded DNA. Negative stain electron microscopy imaging supports a model wherein RADX functions by capping and restricting the growing ends of RAD51 filaments. In summary, our findings provide a comprehensive understanding of the regulatory mechanisms governing RAD51 nucleofilament dynamics by RADX, emphasizing its crucial role in coordinating replication fork stability and genome integrity. This knowledge not only contributes to the fundamental understanding of cellular processes but also offers insights into potential therapeutic interventions targeting RAD51-controlled pathways. Citation Format: Madison Adolph, Swati Balakrishnan, Walter Chazin, David Cortez. Mechanistic insights into how RADX regulates RAD51 nucleoprotein filaments to maintain genome stability and control replication stress responses [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA024.

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Lan, Wei-Hsuan, Sheng-Yao Lin, Chih-Yuan Kao, Wen-Hsuan Chang, Hsin-Yi Yeh, Hao-Yen Chang, Peter Chi, and Hung-Wen Li. "Rad51 facilitates filament assembly of meiosis-specific Dmc1 recombinase." Proceedings of the National Academy of Sciences 117, no. 21 (May 13, 2020): 11257–64. http://dx.doi.org/10.1073/pnas.1920368117.

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Dmc1 recombinases are essential to homologous recombination in meiosis. Here, we studied the kinetics of the nucleoprotein filament assembly ofSaccharomyces cerevisiaeDmc1 using single-molecule tethered particle motion experiments and in vitro biochemical assay. ScDmc1 nucleoprotein filaments are less stable than the ScRad51 ones because of the kinetically much reduced nucleation step. The lower nucleation rate of ScDmc1 results from its lower single-stranded DNA (ssDNA) affinity, compared to that of ScRad51. Surprisingly, ScDmc1 nucleates mostly on the DNA structure containing the single-stranded and duplex DNA junction with the allowed extension in the 5′-to-3′ polarity, while ScRad51 nucleation depends strongly on ssDNA lengths. This nucleation preference is also conserved for mammalian RAD51 and DMC1. In addition, ScDmc1 nucleation can be stimulated by short ScRad51 patches, but not by EcRecA ones. Pull-down experiments also confirm the physical interactions of ScDmc1 with ScRad51 in solution, but not with EcRecA. Our results are consistent with a model that Dmc1 nucleation can be facilitated by a structural component (such as DNA junction and protein–protein interaction) and DNA polarity. They provide direct evidence of how Rad51 is required for meiotic recombination and highlight a regulation strategy in Dmc1 nucleoprotein filament assembly.

22

Mazin, Alexander V., Carole J. Bornarth, Jachen A. Solinger, Wolf-Dietrich Heyer, and Stephen C. Kowalczykowski. "Rad54 Protein Is Targeted to Pairing Loci by the Rad51 Nucleoprotein Filament." Molecular Cell 6, no. 3 (September 2000): 583–92. http://dx.doi.org/10.1016/s1097-2765(00)00057-5.

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23

Fornander, Louise H., Axelle Renodon-Cornière, Naoyuki Kuwabara, Kentaro Ito, Yasuhiro Tsutsui, Toshiyuki Shimizu, Hiroshi Iwasaki, Bengt Nordén, and Masayuki Takahashi. "Swi5-Sfr1 protein stimulates Rad51-mediated DNA strand exchange reaction through organization of DNA bases in the presynaptic filament." Nucleic Acids Research 42, no. 4 (December 3, 2013): 2358–65. http://dx.doi.org/10.1093/nar/gkt1257.

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Abstract The Swi5-Sfr1 heterodimer protein stimulates the Rad51-promoted DNA strand exchange reaction, a crucial step in homologous recombination. To clarify how this accessory protein acts on the strand exchange reaction, we have analyzed how the structure of the primary reaction intermediate, the Rad51/single-stranded DNA (ssDNA) complex filament formed in the presence of ATP, is affected by Swi5-Sfr1. Using flow linear dichroism spectroscopy, we observe that the nucleobases of the ssDNA are more perpendicularly aligned to the filament axis in the presence of Swi5-Sfr1, whereas the bases are more randomly oriented in the absence of Swi5-Sfr1. When using a modified version of the natural protein where the N-terminal part of Sfr1 is deleted, which has no affinity for DNA but maintained ability to stimulate the strand exchange reaction, we still observe the improved perpendicular DNA base orientation. This indicates that Swi5-Sfr1 exerts its activating effect through interaction with the Rad51 filament mainly and not with the DNA. We propose that the role of a coplanar alignment of nucleobases induced by Swi5-Sfr1 in the presynaptic Rad51/ssDNA complex is to facilitate the critical matching with an invading double-stranded DNA, hence stimulating the strand exchange reaction.

24

Colavito, S., M. Macris-Kiss, C. Seong, O. Gleeson, E. C. Greene, H. L. Klein, L. Krejci, and P. Sung. "Functional significance of the Rad51-Srs2 complex in Rad51 presynaptic filament disruption." Nucleic Acids Research 37, no. 20 (September 10, 2009): 6754–64. http://dx.doi.org/10.1093/nar/gkp748.

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25

Ogawa, T., X. Yu, A. Shinohara, and E. Egelman. "Similarity of the yeast RAD51 filament to the bacterial RecA filament." Science 259, no. 5103 (March 26, 1993): 1896–99. http://dx.doi.org/10.1126/science.8456314.

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26

Bonilla, Braulio, Sarah R. Hengel, McKenzie K. Grundy, and Kara A. Bernstein. "RAD51 Gene Family Structure and Function." Annual Review of Genetics 54, no. 1 (November 23, 2020): 25–46. http://dx.doi.org/10.1146/annurev-genet-021920-092410.

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Accurate DNA repair and replication are critical for genomic stability and cancer prevention. RAD51 and its gene family are key regulators of DNA fidelity through diverse roles in double-strand break repair, replication stress, and meiosis. RAD51 is an ATPase that forms a nucleoprotein filament on single-stranded DNA. RAD51 has the function of finding and invading homologous DNA sequences to enable accurate and timely DNA repair. Its paralogs, which arose from ancient gene duplications of RAD51, have evolved to regulate and promote RAD51 function. Underscoring its importance, misregulation of RAD51, and its paralogs, is associated with diseases such as cancer and Fanconi anemia. In this review, we focus on the mammalian RAD51 structure and function and highlight the use of model systems to enable mechanistic understanding of RAD51 cellular roles. We also discuss how misregulation of the RAD51 gene family members contributes to disease and consider new approaches to pharmacologically inhibit RAD51.

27

Chabot, Thomas, Alain Defontaine, Damien Marquis, Axelle Renodon-Corniere, Emmanuelle Courtois, Fabrice Fleury, and Yvonnick Cheraud. "New Phosphorylation Sites of Rad51 by c-Met Modulates Presynaptic Filament Stability." Cancers 11, no. 3 (March 23, 2019): 413. http://dx.doi.org/10.3390/cancers11030413.

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Genomic instability through deregulation of DNA repair pathways can initiate cancer and subsequently result in resistance to chemo and radiotherapy. Understanding these biological mechanisms is therefore essential to overcome cancer. RAD51 is the central protein of the Homologous Recombination (HR) DNA repair pathway, which leads to faithful DNA repair of DSBs. The recombinase activity of RAD51 requires nucleofilament formation and is regulated by post-translational modifications such as phosphorylation. In the last decade, studies have suggested the existence of a relationship between receptor tyrosine kinases (RTK) and Homologous Recombination DNA repair. Among these RTK the c-MET receptor is often overexpressed or constitutively activated in many cancer types and its inhibition induces the decrease of HR. In this study, we show for the first time that c-MET is able to phosphorylate the RAD51 protein. We demonstrate in vitro that c-MET phosphorylates four tyrosine residues localized mainly in the subunit-subunit interface of RAD51. Whereas these post-translational modifications do not affect the presynaptic filament formation, they strengthen its stability against the inhibitor effect of the BRC peptide obtained from BRCA2. Taken together, these results confirm the role of these modifications in the regulation of the BRCA2-RAD51 interaction and underline the importance of c-MET in DNA damage response.

28

Alexeev, Andrei, Alexander Mazin, and Stephen C. Kowalczykowski. "Rad54 protein possesses chromatin-remodeling activity stimulated by the Rad51–ssDNA nucleoprotein filament." Nature Structural & Molecular Biology 10, no. 3 (February 10, 2003): 182–86. http://dx.doi.org/10.1038/nsb901.

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29

Jensen, Julia R., and Ryan B. Jensen. "Abstract 5603: Defining the functions of the BRCA2 BRC repeats in modulating RAD51 binding and activity." Cancer Research 84, no. 6_Supplement (March 22, 2024): 5603. http://dx.doi.org/10.1158/1538-7445.am2024-5603.

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Abstract The BRCA2 (Breast Cancer Susceptibility 2) gene is critical for preserving genome integrity by regulating homology-directed repair (HDR) of DNA double-strand breaks (DSBs). Germline mutations in BRCA2 predispose individuals to a high risk for ovarian, breast, prostate, and pancreatic cancer. BRCA2 contains eight BRC repeats that mediate binding to RAD51. It remains unclear how exactly the different BRC repeats regulate RAD51 functions. In our study, we explore the importance of each BRC repeat, their interconnections, and their impact on RAD51 binding and filament stability. We engineered amino acid substitutions into the BRC FxTAS motif required for specific contacts within a hydrophobic binding pocket of RAD51 to disrupt BRC binding to RAD51. We further created mutations in RAD51 (F86E/A89E) that either prevent self-association but retain binding to the BRC repeats or a mutation (K133R) that results in a hyper-stable RAD51 nucleoprotein filament. Using both cell-based models and biochemical analyses, we have begun studies to parse out the specific functions of each BRC repeat. Our ultimate goal is to incorporate single amino acid changes into each BRC repeat within the context of the full-length BRCA2 protein to comprehensively characterize the contribution of each BRC repeat to HDR and response to chemotherapeutics such as PARP inhibitors. Citation Format: Julia R. Jensen, Ryan B. Jensen. Defining the functions of the BRCA2 BRC repeats in modulating RAD51 binding and activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5603.

30

Krejci, Lumir, Stephen Van Komen, Ying Li, Jana Villemain, Mothe Sreedhar Reddy, Hannah Klein, Thomas Ellenberger, and Patrick Sung. "DNA helicase Srs2 disrupts the Rad51 presynaptic filament." Nature 423, no. 6937 (May 2003): 305–9. http://dx.doi.org/10.1038/nature01577.

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31

Amunugama, Ravindra, Yujiong He, Smaranda Willcox, Robert A. Forties, Kang-Sup Shim, Ralf Bundschuh, Yu Luo, Jack Griffith, and Richard Fishel. "RAD51 Protein ATP Cap Regulates Nucleoprotein Filament Stability." Journal of Biological Chemistry 287, no. 12 (January 24, 2012): 8724–36. http://dx.doi.org/10.1074/jbc.m111.239426.

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32

Morrison, Ciaran, Akira Shinohara, Eiichiro Sonoda, Yuko Yamaguchi-Iwai, Minoru Takata, Ralph R. Weichselbaum, and Shunichi Takeda. "The Essential Functions of Human Rad51 Are Independent of ATP Hydrolysis." Molecular and Cellular Biology 19, no. 10 (October 1, 1999): 6891–97. http://dx.doi.org/10.1128/mcb.19.10.6891.

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ABSTRACT Genetic recombination and the repair of double-strand DNA breaks inSaccharomyces cerevisiae require Rad51, a homologue of theEscherichia coli RecA protein. In vitro, Rad51 binds DNA to form an extended nucleoprotein filament and catalyzes the ATP-dependent exchange of DNA between molecules with homologous sequences. Vertebrate Rad51 is essential for cell proliferation. Using site-directed mutagenesis of highly conserved residues of human Rad51 (hRad51) and gene targeting of the RAD51 locus in chicken DT40 cells, we examined the importance of Rad51’s highly conserved ATP-binding domain. Mutant hRad51 incapable of ATP hydrolysis (hRad51K-133R) binds DNA less efficiently than the wild type but catalyzes strand exchange between homologous DNAs. hRad51 does not need to hydrolyze ATP to allow vertebrate cell proliferation, form nuclear foci, or repair radiation-induced DNA damage. However, cells expressing hRad51K-133R show greatly reduced targeted integration frequencies. These findings show that ATP hydrolysis is involved in DNA binding by hRad51 and suggest that the extent of DNA complexed with hRad51 in nucleoprotein influences the efficiency of recombination.

33

Shang, Yongliang, Tao Huang, Hongbin Liu, Yanlei Liu, Heng Liang, Xiaoxia Yu, Mengjing Li, et al. "MEIOK21: a new component of meiotic recombination bridges required for spermatogenesis." Nucleic Acids Research 48, no. 12 (May 28, 2020): 6624–39. http://dx.doi.org/10.1093/nar/gkaa406.

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Abstract Repair of DNA double-strand breaks (DSBs) with homologous chromosomes is a hallmark of meiosis that is mediated by recombination ‘bridges’ between homolog axes. This process requires cooperation of DMC1 and RAD51 to promote homology search and strand exchange. The mechanism(s) regulating DMC1/RAD51-ssDNA nucleoprotein filament and the components of ‘bridges’ remain to be investigated. Here we show that MEIOK21 is a newly identified component of meiotic recombination bridges and is required for efficient formation of DMC1/RAD51 foci. MEIOK21 dynamically localizes on chromosomes from on-axis foci to ‘hanging foci’, then to ‘bridges’, and finally to ‘fused foci’ between homolog axes. Its chromosome localization depends on DSBs. Knockout of Meiok21 decreases the numbers of HSF2BP and DMC1/RAD51 foci, disrupting DSB repair, synapsis and crossover recombination and finally causing male infertility. Therefore, MEIOK21 is a novel recombination factor and probably mediates DMC1/RAD51 recruitment to ssDNA or their stability on chromosomes through physical interaction with HSF2BP.

34

Taylor, Martin R. G., Mário Špírek, Chu Jian Ma, Raffaella Carzaniga, Tohru Takaki, Lucy M. Collinson, Eric C. Greene, Lumir Krejci, and Simon J. Boulton. "A Polar and Nucleotide-Dependent Mechanism of Action for RAD51 Paralogs in RAD51 Filament Remodeling." Molecular Cell 64, no. 5 (December 2016): 926–39. http://dx.doi.org/10.1016/j.molcel.2016.10.020.

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35

Peterson, Shaun E., Yinyin Li, Brian T. Chait, Max E. Gottesman, Richard Baer, and Jean Gautier. "Cdk1 uncouples CtIP-dependent resection and Rad51 filament formation during M-phase double-strand break repair." Journal of Cell Biology 194, no. 5 (September 5, 2011): 705–20. http://dx.doi.org/10.1083/jcb.201103103.

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DNA double-strand break (DSB) resection, which results in RPA-bound single-stranded DNA (ssDNA), is activated in S phase by Cdk2. RPA-ssDNA activates the ATR-dependent checkpoint and homology-directed repair (HDR) via Rad51-dependent mechanisms. On the other hand, the fate of DSBs sustained during vertebrate M phase is largely unknown. We use cell-free Xenopus laevis egg extracts to examine the recruitment of proteins to chromatin after DSB formation. We find that S-phase extract recapitulates a two-step resection mechanism. M-phase chromosomes are also resected in cell-free extracts and cultured human cells. In contrast to the events in S phase, M-phase resection is solely dependent on MRN-CtIP. Despite generation of RPA-ssDNA, M-phase resection does not lead to ATR activation or Rad51 chromatin association. Remarkably, we find that Cdk1 permits resection by phosphorylation of CtIP but also prevents Rad51 binding to the resected ends. We have thus identified Cdk1 as a critical regulator of DSB repair in M phase. Cdk1 induces persistent ssDNA-RPA overhangs in M phase, thereby preventing both classical NHEJ and Rad51-dependent HDR.

36

Petiot, Valentine, Charles I. White, and Olivier Da Ines. "DNA-binding site II is required for RAD51 recombinogenic activity inArabidopsis thaliana." Life Science Alliance 7, no. 8 (May 20, 2024): e202402701. http://dx.doi.org/10.26508/lsa.202402701.

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Homologous recombination is a major pathway for the repair of DNA double strand breaks, essential both to maintain genomic integrity and to generate genetic diversity. Mechanistically, homologous recombination involves the use of a homologous DNA molecule as a template to repair the break. In eukaryotes, the search for and invasion of the homologous DNA molecule is carried out by two recombinases, RAD51 in somatic cells and RAD51 and DMC1 in meiotic cells. During recombination, the recombinases bind overhanging single-stranded DNA ends to form a nucleoprotein filament, which is the active species in promoting DNA invasion and strand exchange. RAD51 and DMC1 carry two major DNA-binding sites—essential for nucleofilament formation and DNA strand exchange, respectively. Here, we show that the function of RAD51 DNA-binding site II is conserved in the plant, Arabidopsis. Mutation of three key amino acids in site II does not affect RAD51 nucleofilament formation but inhibits its recombinogenic activity, analogous to results from studies of the yeast and human proteins. We further confirm that recombinogenic function of RAD51 DNA-binding site II is not required for meiotic double-strand break repair when DMC1 is present. The ArabidopsisAtRAD51-II3Aseparation of function mutant shows a dominant negative phenotype, pointing to distinct biochemical properties of eukaryotic RAD51 proteins.

37

Adolph, Madison B., Taha M. Mohamed, Swati Balakrishnan, Chaoyou Xue, Florian Morati, Mauro Modesti, Eric C. Greene, Walter J. Chazin, and David Cortez. "RADX controls RAD51 filament dynamics to regulate replication fork stability." Molecular Cell 81, no. 5 (March 2021): 1074–83. http://dx.doi.org/10.1016/j.molcel.2020.12.036.

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38

Lee, M., J. Lipfert, H. Sanchez, C. Wyman, and N. H. Dekker. "Structural and torsional properties of the RAD51-dsDNA nucleoprotein filament." Nucleic Acids Research 41, no. 14 (May 22, 2013): 7023–30. http://dx.doi.org/10.1093/nar/gkt425.

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39

Qiu, Yupeng, Edwin Anthony, Timothy Lohman, and Sua Myong. "Srs2 Prevents Rad51 Filament Formation by Repetitive Scrunching of DNA." Biophysical Journal 104, no. 2 (January 2013): 75a. http://dx.doi.org/10.1016/j.bpj.2012.11.452.

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40

Candelli, Andrea, Jan T. Holhausen, Martin Depken, Mariella M. Franker, Joseph Maman, Luca Pellegrini, Mauro Modesti, Claire Wyman, Gijs Wuite, and Erwin J. Peterman. "RAD51-Nucleoprotein Filament Assembly Quantified at the Single-Molecule Level." Biophysical Journal 104, no. 2 (January 2013): 369a. http://dx.doi.org/10.1016/j.bpj.2012.11.2049.

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41

Martinez, Juan S., Catharina von Nicolai, Taeho Kim, Åsa Ehlén, Alexander V. Mazin, Stephen C. Kowalczykowski, and Aura Carreira. "BRCA2 regulates DMC1-mediated recombination through the BRC repeats." Proceedings of the National Academy of Sciences 113, no. 13 (March 14, 2016): 3515–20. http://dx.doi.org/10.1073/pnas.1601691113.

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In somatic cells, BRCA2 is needed for RAD51-mediated homologous recombination. The meiosis-specific DNA strand exchange protein, DMC1, promotes the formation of DNA strand invasion products (joint molecules) between homologous molecules in a fashion similar to RAD51. BRCA2 interacts directly with both human RAD51 and DMC1; in the case of RAD51, this interaction results in stimulation of RAD51-promoted DNA strand exchange. However, for DMC1, little is known regarding the basis and functional consequences of its interaction with BRCA2. Here we report that human DMC1 interacts directly with each of the BRC repeats of BRCA2, albeit most tightly with repeats 1–3 and 6–8. However, BRC1–3 bind with higher affinity to RAD51 than to DMC1, whereas BRC6–8 bind with higher affinity to DMC1, providing potential spatial organization to nascent filament formation. With the exception of BRC4, each BRC repeat stimulates joint molecule formation by DMC1. The basis for this stimulation is an enhancement of DMC1–ssDNA complex formation by the stimulatory BRC repeats. Lastly, we demonstrate that full-length BRCA2 protein stimulates DMC1-mediated DNA strand exchange between RPA–ssDNA complexes and duplex DNA, thus identifying BRCA2 as a mediator of DMC1 recombination function. Collectively, our results suggest unique and specialized functions for the BRC motifs of BRCA2 in promoting homologous recombination in meiotic and mitotic cells.

42

Ma, Chu Jian, Bryan Gibb, YoungHo Kwon, Patrick Sung, and Eric C. Greene. "Protein dynamics of human RPA and RAD51 on ssDNA during assembly and disassembly of the RAD51 filament." Nucleic Acids Research 45, no. 2 (November 29, 2016): 749–61. http://dx.doi.org/10.1093/nar/gkw1125.

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43

Galkin, Vitold E., Yan Wu, Xiao-Ping Zhang, Xinguo Qian, Yujiong He, Xiong Yu, Wolf-Dietrich Heyer, Yu Luo, and Edward H. Egelman. "The Rad51/RadA N-Terminal Domain Activates Nucleoprotein Filament ATPase Activity." Structure 14, no. 6 (June 2006): 983–92. http://dx.doi.org/10.1016/j.str.2006.04.001.

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44

Seong, Changhyun, Sierra Colavito, Youngho Kwon, Patrick Sung, and Lumir Krejci. "Regulation of Rad51 Recombinase Presynaptic Filament Assembly via Interactions with the Rad52 Mediator and the Srs2 Anti-recombinase." Journal of Biological Chemistry 284, no. 36 (July 15, 2009): 24363–71. http://dx.doi.org/10.1074/jbc.m109.032953.

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45

Khade, Nilesh V., and Tomohiko Sugiyama. "Roles of C-Terminal Region of Yeast and Human Rad52 in Rad51-Nucleoprotein Filament Formation and ssDNA Annealing." PLOS ONE 11, no. 6 (June 30, 2016): e0158436. http://dx.doi.org/10.1371/journal.pone.0158436.

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46

Seong, Changhyun, Sierra Colavito, Youngho Kwon, Patrick Sung, and Lumir Krejci. "Regulation of Rad51 recombinase presynaptic filament assembly via interactions with the Rad52 mediator and the Srs2 anti-recombinase." Journal of Biological Chemistry 287, no. 15 (April 6, 2012): 12154. http://dx.doi.org/10.1074/jbc.a109.032953.

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47

Nifontova, Galina, Cathy Charlier, Nizar Ayadi, Fabrice Fleury, Alexander Karaulov, Alyona Sukhanova, and Igor Nabiev. "Photonic Crystal Surface Mode Real-Time Imaging of RAD51 DNA Repair Protein Interaction with the ssDNA Substrate." Biosensors 14, no. 1 (January 14, 2024): 43. http://dx.doi.org/10.3390/bios14010043.

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Photonic crystals (PCs) are promising tools for label-free sensing in drug discovery screening, diagnostics, and analysis of ligand–receptor interactions. Imaging of PC surface modes has emerged as a novel approach to the detection of multiple binding events at the sensor surface. PC surface modification and decoration with recognition units yield an interface providing the highly sensitive detection of cancer biomarkers, antibodies, and oligonucleotides. The RAD51 protein plays a central role in DNA repair via the homologous recombination pathway. This recombinase is essential for the genome stability and its overexpression is often correlated with aggressive cancer. RAD51 is therefore a potential target in the therapeutic strategy for cancer. Here, we report the designing of a PC-based array sensor for real-time monitoring of oligonucleotide–RAD51 recruitment by means of surface mode imaging and validation of the concept of this approach. Our data demonstrate that the designed biosensor ensures the highly sensitive multiplexed analysis of association–dissociation events and detection of the biomarker of DNA damage using a microfluidic PC array. The obtained results highlight the potential of the developed technique for testing the functionality of candidate drugs, discovering new molecular targets and drug entities. This paves the way to further adaption and bioanalytical use of the biosensor for high-content screening to identify new DNA repair inhibitor drugs targeting the RAD51 nucleoprotein filament or to discover new molecular targets.

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Tsai, Shang-Pu, Guan-Chin Su, Sheng-Wei Lin, Chan-I. Chung, Xiaoyu Xue, Myun Hwa Dunlop, Yufuko Akamatsu, Maria Jasin, Patrick Sung, and Peter Chi. "Rad51 presynaptic filament stabilization function of the mouse Swi5–Sfr1 heterodimeric complex." Nucleic Acids Research 40, no. 14 (April 9, 2012): 6558–69. http://dx.doi.org/10.1093/nar/gks305.

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49

Candelli, Andrea, Jan Thomas Holthausen, Martin Depken, Ineke Brouwer, Mariëlla A. M. Franker, Margherita Marchetti, Iddo Heller, et al. "Visualization and quantification of nascent RAD51 filament formation at single-monomer resolution." Proceedings of the National Academy of Sciences 111, no. 42 (October 6, 2014): 15090–95. http://dx.doi.org/10.1073/pnas.1307824111.

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50

Bernstein, Kara A., Robert J. D. Reid, Ivana Sunjevaric, Kimberly Demuth, Rebecca C. Burgess, and Rodney Rothstein. "The Shu complex, which contains Rad51 paralogues, promotes DNA repair through inhibition of the Srs2 anti-recombinase." Molecular Biology of the Cell 22, no. 9 (May 2011): 1599–607. http://dx.doi.org/10.1091/mbc.e10-08-0691.

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The Shu complex, which contains RAD51 paralogues, is involved in the decision between homologous recombination and error-prone repair. We discovered a link to ribosomal DNA (rDNA) recombination when we found an interaction between one member of the Shu complex, SHU1, and UAF30, a component of the upstream activating factor complex (UAF), which regulates rDNA transcription. In the absence of Uaf30, rDNA copy number increases, and this increase depends on several functional subunits of the Shu complex. Furthermore, in the absence of Uaf30, we find that Shu1 and Srs2, an anti-recombinase DNA helicase with which the Shu complex physically interacts, act in the same pathway regulating rDNA recombination. In addition, Shu1 modulates Srs2 recruitment to both induced and spontaneous foci correlating with a decrease in Rad51 foci, demonstrating that the Shu complex is an important regulator of Srs2 activity. Last, we show that Shu1 regulation of Srs2 to double-strand breaks is not restricted to the rDNA, indicating a more general function for the Shu complex in the regulation of Srs2. We propose that the Shu complex shifts the balance of repair toward Rad51 filament stabilization by inhibiting the disassembly reaction of Srs2.

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