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Автор: Grafiati

Опубліковано: 7 липня 2024

Оновлено: 7 липня 2024

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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

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.

4

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.

5

Andriuskevicius, Tadas, Anton Dubenko, and Svetlana Makovets. "The Inability to Disassemble Rad51 Nucleoprotein Filaments Leads to Aberrant Mitosis and Cell Death." Biomedicines 11, no. 5 (May 15, 2023): 1450. http://dx.doi.org/10.3390/biomedicines11051450.

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The proper maintenance of genetic material is essential for the survival of living organisms. One of the main safeguards of genome stability is homologous recombination involved in the faithful repair of DNA double-strand breaks, the restoration of collapsed replication forks, and the bypass of replication barriers. Homologous recombination relies on the formation of Rad51 nucleoprotein filaments which are responsible for the homology-based interactions between DNA strands. Here, we demonstrate that without the regulation of these filaments by Srs2 and Rad54, which are known to remove Rad51 from single-stranded and double-stranded DNA, respectively, the filaments strongly inhibit damage-associated DNA synthesis during DNA repair. Furthermore, this regulation is essential for cell survival under normal growth conditions, as in the srs2Δ rad54Δ mutants, unregulated Rad51 nucleoprotein filaments cause activation of the DNA damage checkpoint, formation of mitotic bridges, and loss of genetic material. These genome instability features may stem from the problems at stalled replication forks as the lack of Srs2 and Rad54 in the presence of Rad51 nucleoprotein filaments impedes cell recovery from replication stress. This study demonstrates that the timely and efficient disassembly of recombination machinery is essential for genome maintenance and cell survival.

6

Takata, Minoru, Masao S. Sasaki, Eiichiro Sonoda, Toru Fukushima, Ciaran Morrison, Joanna S. Albala, Sigrid M. A. Swagemakers, Roland Kanaar, Larry H. Thompson, and Shunichi Takeda. "The Rad51 Paralog Rad51B Promotes Homologous Recombinational Repair." Molecular and Cellular Biology 20, no. 17 (September 1, 2000): 6476–82. http://dx.doi.org/10.1128/mcb.20.17.6476-6482.2000.

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ABSTRACT The highly conserved Saccharomyces cerevisiae Rad51 protein plays a central role in both mitotic and meiotic homologous DNA recombination. Seven members of the Rad51 family have been identified in vertebrate cells, including Rad51, Dmc1, and five Rad51-related proteins referred to as Rad51 paralogs, which share 20 to 30% sequence identity with Rad51. In chicken B lymphocyte DT40 cells, we generated a mutant with RAD51B/RAD51L1, a member of the Rad51 family, knocked out. RAD51B −/− cells are viable, although spontaneous chromosomal aberrations kill about 20% of the cells in each cell cycle. Rad51B deficiency impairs homologous recombinational repair (HRR), as measured by targeted integration, sister chromatid exchange, and intragenic recombination at the immunoglobulin locus. RAD51B −/− cells are quite sensitive to the cross-linking agents cisplatin and mitomycin C and mildly sensitive to γ-rays. The formation of damage-induced Rad51 nuclear foci is much reduced in RAD51B −/−cells, suggesting that Rad51B promotes the assembly of Rad51 nucleoprotein filaments during HRR. These findings show that Rad51B is important for repairing various types of DNA lesions and maintaining chromosome integrity.

7

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.

8

Raschle, Markus, Stephen Van Komen, Peter Chi, Tom Ellenberger, and Patrick Sung. "Multiple Interactions with the Rad51 Recombinase Govern the Homologous Recombination Function of Rad54." Journal of Biological Chemistry 279, no. 50 (September 30, 2004): 51973–80. http://dx.doi.org/10.1074/jbc.m410101200.

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In eukaryotes, Rad51 and Rad54 functionally cooperate to mediate homologous recombination and the repair of damaged chromosomes by recombination. Rad51, the eukaryotic counterpart of the bacterial RecA recombinase, forms filaments on single-stranded DNA that are capable of pairing the bound DNA with a homologous double-stranded donor to yield joint molecules. Rad54 enhances the homologous DNA pairing reaction, and this stimulatory effect involves a physical interaction with Rad51. Correspondingly, the ability of Rad54 to hydrolyze ATP and introduce superhelical tension into covalently closed circular plasmid DNA is stimulated by Rad51. By controlled proteolysis, we show that the amino-terminal region of yeast Rad54 is rather unstructured. Truncation mutations that delete the N-terminal 113 or 129 amino acid residues of Rad54 attenuate or ablate physical and functional interactions with Rad51 under physiological ionic strength, respectively. Surprisingly, under less stringent conditions, the Rad54 Δ129 protein can interact with Rad51 in affinity pull-down and functional assays. These results highlight the functional importance of the N-terminal Rad51 interaction domain of Rad54 and reveal that Rad54 contacts Rad51 through separable epitopes.

9

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.

10

Paliwal, Shreya, Radhakrishnan Kanagaraj, Andreas Sturzenegger, Kamila Burdova, and Pavel Janscak. "Human RECQ5 helicase promotes repair of DNA double-strand breaks by synthesis-dependent strand annealing." Nucleic Acids Research 42, no. 4 (December 5, 2013): 2380–90. http://dx.doi.org/10.1093/nar/gkt1263.

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Abstract Most mitotic homologous recombination (HR) events proceed via a synthesis-dependent strand annealing mechanism to avoid crossing over, which may give rise to chromosomal rearrangements and loss of heterozygosity. The molecular mechanisms controlling HR sub-pathway choice are poorly understood. Here, we show that human RECQ5, a DNA helicase that can disrupt RAD51 nucleoprotein filaments, promotes formation of non-crossover products during DNA double-strand break-induced HR and counteracts the inhibitory effect of RAD51 on RAD52-mediated DNA annealing in vitro and in vivo. Moreover, we demonstrate that RECQ5 deficiency is associated with an increased occupancy of RAD51 at a double-strand break site, and it also causes an elevation of sister chromatid exchanges on inactivation of the Holliday junction dissolution pathway or on induction of a high load of DNA damage in the cell. Collectively, our findings suggest that RECQ5 acts during the post-synaptic phase of synthesis-dependent strand annealing to prevent formation of aberrant RAD51 filaments on the extended invading strand, thus limiting its channeling into potentially hazardous crossover pathway of HR.

11

Sauvageau, Synthia, Alicja Z. Stasiak, Isabelle Banville, Mickaël Ploquin, Andrzej Stasiak, and Jean-Yves Masson. "Fission Yeast Rad51 and Dmc1, Two Efficient DNA Recombinases Forming Helical Nucleoprotein Filaments." Molecular and Cellular Biology 25, no. 11 (June 1, 2005): 4377–87. http://dx.doi.org/10.1128/mcb.25.11.4377-4387.2005.

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ABSTRACT Homologous recombination is important for the repair of double-strand breaks during meiosis. Eukaryotic cells require two homologs of Escherichia coli RecA protein, Rad51 and Dmc1, for meiotic recombination. To date, it is not clear, at the biochemical level, why two homologs of RecA are necessary during meiosis. To gain insight into this, we purified Schizosaccharomyces pombe Rad51 and Dmc1 to homogeneity. Purified Rad51 and Dmc1 form homo-oligomers, bind single-stranded DNA preferentially, and exhibit DNA-stimulated ATPase activity. Both Rad51 and Dmc1 promote the renaturation of complementary single-stranded DNA. Importantly, Rad51 and Dmc1 proteins catalyze ATP-dependent strand exchange reactions with homologous duplex DNA. Electron microscopy reveals that both S. pombe Rad51 and Dmc1 form nucleoprotein filaments. Rad51 formed helical nucleoprotein filaments on single-stranded DNA, whereas Dmc1 was found in two forms, as helical filaments and also as stacked rings. These results demonstrate that Rad51 and Dmc1 are both efficient recombinases in lower eukaryotes and reveal closer functional and structural similarities between the meiotic recombinase Dmc1 and Rad51. The DNA strand exchange activity of both Rad51 and Dmc1 is most likely critical for proper meiotic DNA double-strand break repair in lower eukaryotes.

12

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.

13

Chang, Hao-Yen, Chia-Yi Lee, Chih-Hao Lu, Wei Lee, Han-Lin Yang, Hsin-Yi Yeh, Hung-Wen Li, and Peter Chi. "Microcephaly family protein MCPH1 stabilizes RAD51 filaments." Nucleic Acids Research 48, no. 16 (July 31, 2020): 9135–46. http://dx.doi.org/10.1093/nar/gkaa636.

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Abstract Microcephalin 1 (MCPH1) was identified from genetic mutations in patients with primary autosomal recessive microcephaly. In response to DNA double-strand breaks (DSBs), MCPH1 forms damage-induced foci and recruits BRCA2–RAD51 complex, a key component of the DSB repair machinery for homologous recombination (HR), to damage sites. Accordingly, the efficiency of HR is significantly attenuated upon depletion of MCPH1. The biochemical characteristics of MCPH1 and its functional interaction with the HR machinery had remained unclear due to lack of highly purified MCPH1 recombinant protein for functional study. Here, we established a mammalian expression system to express and purify MCPH1 protein. We show that MCPH1 is a bona fide DNA-binding protein and provide direct biochemical analysis of this MCPH family protein. Furthermore, we reveal that MCPH1 directly interacts with RAD51 at multiple contact points, providing evidence for how MCPH1 physically engages with the HR machinery. Importantly, we demonstrate that MCPH1 enhances the stability of RAD51 on single-strand DNA, a prerequisite step for RAD51-mediated recombination. Single-molecule tethered particle motion analysis showed a ∼2-fold increase in the lifetime of RAD51–ssDNA filaments in the presence of MCPH1. Thus, our study demonstrates direct crosstalk between microcephaly protein MCPH1 and the recombination component RAD51 for DSB repair.

14

Taylor, Martin R. G., Mário Špírek, Kathy R. Chaurasiya, Jordan D. Ward, Raffaella Carzaniga, Xiong Yu, Edward H. Egelman, et al. "Rad51 Paralogs Remodel Pre-synaptic Rad51 Filaments to Stimulate Homologous Recombination." Cell 162, no. 2 (July 2015): 271–86. http://dx.doi.org/10.1016/j.cell.2015.06.015.

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15

Orhan, Esin, Carolina Velazquez, Imene Tabet, Claude Sardet, and Charles Theillet. "Regulation of RAD51 at the Transcriptional and Functional Levels: What Prospects for Cancer Therapy?" Cancers 13, no. 12 (June 11, 2021): 2930. http://dx.doi.org/10.3390/cancers13122930.

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The RAD51 recombinase is a critical effector of Homologous Recombination (HR), which is an essential DNA repair mechanism for double-strand breaks. The RAD51 protein is recruited onto the DNA break by BRCA2 and forms homopolymeric filaments that invade the homologous chromatid and use it as a template for repair. RAD51 filaments are detectable by immunofluorescence as distinct foci in the cell nucleus, and their presence is a read out of HR proficiency. RAD51 is an essential gene, protecting cells from genetic instability. Its expression is low and tightly regulated in normal cells and, contrastingly, elevated in a large fraction of cancers, where its level of expression and activity have been linked with sensitivity to genotoxic treatment. In particular, BRCA-deficient tumors show reduced or obliterated RAD51 foci formation and increased sensitivity to platinum salt or PARP inhibitors. However, resistance to treatment sets in rapidly and is frequently based on a complete or partial restoration of RAD51 foci formation. Consequently, RAD51 could be a highly valuable therapeutic target. Here, we review the multiple levels of regulation that impact the transcription of the RAD51 gene, as well as the post-translational modifications that determine its expression level, recruitment on DNA damage sites and the efficient formation of homofilaments. Some of these regulation levels may be targeted and their impact on cancer cell survival discussed.

16

Ziesel, Andrew, Qixuan Weng, Jasvinder S. Ahuja, Abhishek Bhattacharya, Raunak Dutta, Evan Cheng, G. Valentin Börner, Michael Lichten, and Nancy M. Hollingsworth. "Rad51-mediated interhomolog recombination during budding yeast meiosis is promoted by the meiotic recombination checkpoint and the conserved Pif1 helicase." PLOS Genetics 18, no. 12 (December 12, 2022): e1010407. http://dx.doi.org/10.1371/journal.pgen.1010407.

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During meiosis, recombination between homologous chromosomes (homologs) generates crossovers that promote proper segregation at the first meiotic division. Recombination is initiated by Spo11-catalyzed DNA double strand breaks (DSBs). 5’ end resection of the DSBs creates 3’ single strand tails that two recombinases, Rad51 and Dmc1, bind to form presynaptic filaments that search for homology, mediate strand invasion and generate displacement loops (D-loops). D-loop processing then forms crossover and non-crossover recombinants. Meiotic recombination occurs in two temporally distinct phases. During Phase 1, Rad51 is inhibited and Dmc1 mediates the interhomolog recombination that promotes homolog synapsis. In Phase 2, Rad51 becomes active and functions with Rad54 to repair residual DSBs, making increasing use of sister chromatids. The transition from Phase 1 to Phase 2 is controlled by the meiotic recombination checkpoint through the meiosis-specific effector kinase Mek1. This work shows that constitutive activation of Rad51 in Phase 1 results in a subset of DSBs being repaired by a Rad51-mediated interhomolog recombination pathway that is distinct from that of Dmc1. Strand invasion intermediates generated by Rad51 require more time to be processed into recombinants, resulting in a meiotic recombination checkpoint delay in prophase I. Without the checkpoint, Rad51-generated intermediates are more likely to involve a sister chromatid, thereby increasing Meiosis I chromosome nondisjunction. This Rad51 interhomolog recombination pathway is specifically promoted by the conserved 5’-3’ helicase PIF1 and its paralog, RRM3 and requires Pif1 helicase activity and its interaction with PCNA. This work demonstrates that (1) inhibition of Rad51 during Phase 1 is important to prevent competition with Dmc1 for DSB repair, (2) Rad51-mediated meiotic recombination intermediates are initially processed differently than those made by Dmc1, and (3) the meiotic recombination checkpoint provides time during prophase 1 for processing of Rad51-generated recombination intermediates.

17

Solinger, Jachen A., Konstantin Kiianitsa, and Wolf-Dietrich Heyer. "Rad54, a Swi2/Snf2-like Recombinational Repair Protein, Disassembles Rad51:dsDNA Filaments." Molecular Cell 10, no. 5 (November 2002): 1175–88. http://dx.doi.org/10.1016/s1097-2765(02)00743-8.

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18

Robertson, R. B., D. N. Moses, Y. Kwon, P. Chan, P. Chi, H. Klein, P. Sung, and E. C. Greene. "Structural transitions within human Rad51 nucleoprotein filaments." Proceedings of the National Academy of Sciences 106, no. 31 (July 21, 2009): 12688–93. http://dx.doi.org/10.1073/pnas.0811465106.

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19

Galkin, V. E., F. Esashi, X. Yu, S. Yang, S. C. West, and E. H. Egelman. "BRCA2 BRC motifs bind RAD51-DNA filaments." Proceedings of the National Academy of Sciences 102, no. 24 (June 3, 2005): 8537–42. http://dx.doi.org/10.1073/pnas.0407266102.

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20

Tsai, Cheng-ting. "Swi5-Sfr1 Stabilizes Formation of RAD51 Nucleoprotein Filaments." Biophysical Journal 102, no. 3 (January 2012): 280a. http://dx.doi.org/10.1016/j.bpj.2011.11.1548.

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21

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.

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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.

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van Mameren, Joost, Mauro Modesti, Roland Kanaar, Claire Wyman, Erwin J. G. Peterman, and Gijs J. L. Wuite. "Counting RAD51 proteins disassembling from nucleoprotein filaments under tension." Nature 457, no. 7230 (December 7, 2008): 745–48. http://dx.doi.org/10.1038/nature07581.

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24

Sheridan, Sean D., Xiong Yu, Robyn Roth, John E. Heuser, Michael G. Sehorn, Patrick Sung, Edward H. Egelman, and Douglas K. Bishop. "A comparative analysis of Dmc1 and Rad51 nucleoprotein filaments." Nucleic Acids Research 36, no. 12 (June 4, 2008): 4057–66. http://dx.doi.org/10.1093/nar/gkn352.

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25

Forget, Anthony L., and Stephen C. Kowalczykowski. "Single-molecule imaging brings Rad51 nucleoprotein filaments into focus." Trends in Cell Biology 20, no. 5 (May 2010): 269–76. http://dx.doi.org/10.1016/j.tcb.2010.02.004.

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van Mameren, Joost, Mauro Modesti, Ronald Kanaar, Wyman Clair, Erwin J. G. Peterman, and Gijs J. L. Wuite. "Counting RAD51 Proteins Disassembling from Nucleoprotein Filaments Under Tension." Biophysical Journal 98, no. 3 (January 2010): 663a. http://dx.doi.org/10.1016/j.bpj.2009.12.3637.

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27

Robertson, Ragan B., Dana N. Moses, YoungHo Kwon, Pamela Chan, Weixing Zhao, Peter Chi, Hannah Klein, Patrick Sung, and Eric C. Greene. "Visualizing the Disassembly of S. cerevisiae Rad51 Nucleoprotein Filaments." Journal of Molecular Biology 388, no. 4 (May 2009): 703–20. http://dx.doi.org/10.1016/j.jmb.2009.03.049.

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Esta, Aline, Emilie Ma, Pauline Dupaigne, Laurent Maloisel, Raphaël Guerois, Eric Le Cam, Xavier Veaute, and Eric Coïc. "Rad52 Sumoylation Prevents the Toxicity of Unproductive Rad51 Filaments Independently of the Anti-Recombinase Srs2." PLoS Genetics 9, no. 10 (October 10, 2013): e1003833. http://dx.doi.org/10.1371/journal.pgen.1003833.

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Misova, Ivana, Alexandra Pitelova, Jaroslav Budis, Juraj Gazdarica, Tatiana Sedlackova, Anna Jordakova, Zsigmond Benko, et al. "Repression of a large number of genes requires interplay between homologous recombination and HIRA." Nucleic Acids Research 49, no. 4 (January 28, 2021): 1914–34. http://dx.doi.org/10.1093/nar/gkab027.

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AbstractDuring homologous recombination, Dbl2 protein is required for localisation of Fbh1, an F-box helicase that efficiently dismantles Rad51–DNA filaments. RNA-seq analysis of dbl2Δ transcriptome showed that the dbl2 deletion results in upregulation of more than 500 loci in Schizosaccharomyces pombe. Compared with the loci with no change in expression, the misregulated loci in dbl2Δ are closer to long terminal and long tandem repeats. Furthermore, the misregulated loci overlap with antisense transcripts, retrotransposons, meiotic genes and genes located in subtelomeric regions. A comparison of the expression profiles revealed that Dbl2 represses the same type of genes as the HIRA histone chaperone complex. Although dbl2 deletion does not alleviate centromeric or telomeric silencing, it suppresses the silencing defect at the outer centromere caused by deletion of hip1 and slm9 genes encoding subunits of the HIRA complex. Moreover, our analyses revealed that cells lacking dbl2 show a slight increase of nucleosomes at transcription start sites and increased levels of methylated histone H3 (H3K9me2) at centromeres, subtelomeres, rDNA regions and long terminal repeats. Finally, we show that other proteins involved in homologous recombination, such as Fbh1, Rad51, Mus81 and Rad54, participate in the same gene repression pathway.

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Veaute, Xavier, Josette Jeusset, Christine Soustelle, Stephen C. Kowalczykowski, Eric Le Cam, and Francis Fabre. "The Srs2 helicase prevents recombination by disrupting Rad51 nucleoprotein filaments." Nature 423, no. 6937 (May 2003): 309–12. http://dx.doi.org/10.1038/nature01585.

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31

Fornander, Louise H., Karolin Frykholm, Joachim Fritzsche, Joshua Araya, Philip Nevin, Erik Werner, Ali Çakır, et al. "Visualizing the Nonhomogeneous Structure of RAD51 Filaments Using Nanofluidic Channels." Langmuir 32, no. 33 (August 12, 2016): 8403–12. http://dx.doi.org/10.1021/acs.langmuir.6b01877.

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32

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.

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Antony, Edwin, Eric J. Tomko, Qi Xiao, Lumir Krejci, Timothy M. Lohman, and Tom Ellenberger. "Srs2 Disassembles Rad51 Filaments by a Protein-Protein Interaction Triggering ATP Turnover and Dissociation of Rad51 from DNA." Molecular Cell 35, no. 1 (July 2009): 105–15. http://dx.doi.org/10.1016/j.molcel.2009.05.026.

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34

Yu, X., V. Galkin, W.-D. Heyer, L. Yu, and E. Egelman. "The Function of N-terminal Domain in RadA/Rad51-DNA Filaments." Microscopy and Microanalysis 12, S02 (July 31, 2006): 420–21. http://dx.doi.org/10.1017/s1431927606068401.

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35

Prasad, Tekkatte Krishnamurthy, Caitlyn C. Yeykal, and Eric C. Greene. "Visualizing the Assembly of Human Rad51 Filaments on Double-stranded DNA." Journal of Molecular Biology 363, no. 3 (October 2006): 713–28. http://dx.doi.org/10.1016/j.jmb.2006.08.046.

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Fornander, Louise Helena, Fredrik Persson, Joachim Fritzsche, Joshua Araya, Philip Nevin, Penny Beuning, Mauro Modesti, Karolin Frykholm, and Fredrik Westerlund. "Using Nanofluidic Channels to Probe the Dynamics of Rad51-DNA Filaments." Biophysical Journal 106, no. 2 (January 2014): 692a—693a. http://dx.doi.org/10.1016/j.bpj.2013.11.3830.

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Crickard, J. Brooks, Chaoyou Xue, Weibin Wang, Youngho Kwon, Patrick Sung, and Eric C. Greene. "The RecQ helicase Sgs1 drives ATP-dependent disruption of Rad51 filaments." Nucleic Acids Research 47, no. 9 (March 27, 2019): 4694–706. http://dx.doi.org/10.1093/nar/gkz186.

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38

Alekseev, Aleksandr, Galina Cherevatenko, Maksim Serdakov, Georgii Pobegalov, Alexander Yakimov, Irina Bakhlanova, Dmitry Baitin, and Mikhail Khodorkovskii. "Single-Molecule Insights into ATP-Dependent Conformational Dynamics of Nucleoprotein Filaments of Deinococcus radiodurans RecA." International Journal of Molecular Sciences 21, no. 19 (October 7, 2020): 7389. http://dx.doi.org/10.3390/ijms21197389.

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Deinococcus radiodurans (Dr) has one of the most robust DNA repair systems, which is capable of withstanding extreme doses of ionizing radiation and other sources of DNA damage. DrRecA, a central enzyme of recombinational DNA repair, is essential for extreme radioresistance. In the presence of ATP, DrRecA forms nucleoprotein filaments on DNA, similar to other bacterial RecA and eukaryotic DNA strand exchange proteins. However, DrRecA catalyzes DNA strand exchange in a unique reverse pathway. Here, we study the dynamics of DrRecA filaments formed on individual molecules of duplex and single-stranded DNA, and we follow conformational transitions triggered by ATP hydrolysis. Our results reveal that ATP hydrolysis promotes rapid DrRecA dissociation from duplex DNA, whereas on single-stranded DNA, DrRecA filaments interconvert between stretched and compressed conformations, which is a behavior shared by E. coli RecA and human Rad51. This indicates a high conservation of conformational switching in nucleoprotein filaments and suggests that additional factors might contribute to an inverse pathway of DrRecA strand exchange.

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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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40

Sanchez, H., A. Kertokalio, S. van Rossum-Fikkert, R. Kanaar, and C. Wyman. "Combined optical and topographic imaging reveals different arrangements of human RAD54 with presynaptic and postsynaptic RAD51-DNA filaments." Proceedings of the National Academy of Sciences 110, no. 28 (June 25, 2013): 11385–90. http://dx.doi.org/10.1073/pnas.1306467110.

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41

Takahashi, Masayuki, and Bengt Norden. "Linear Dichroism Measurements for the Study of Protein-DNA Interactions." International Journal of Molecular Sciences 24, no. 22 (November 8, 2023): 16092. http://dx.doi.org/10.3390/ijms242216092.

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Linear dichroism (LD) is a differential polarized light absorption spectroscopy used for studying filamentous molecules such as DNA and protein filaments. In this study, we review the applications of LD for the analysis of DNA-protein interactions. LD signals can be measured in a solution by aligning the sample using flow-induced shear force or a strong electric field. The signal generated is related to the local orientation of chromophores, such as DNA bases, relative to the filament axis. LD can thus assess the tilt and roll of DNA bases and distinguish intercalating from groove-binding ligands. The intensity of the LD signal depends upon the degree of macroscopic orientation. Therefore, DNA shortening and bending can be detected by a decrease in LD signal intensity. As examples of LD applications, we present a kinetic study of DNA digestion by restriction enzymes and structural analyses of homologous recombination intermediates, i.e., RecA and Rad51 recombinase complexes with single-stranded DNA. LD shows that the DNA bases in these complexes are preferentially oriented perpendicular to the filament axis only in the presence of activators, suggesting the importance of organized base orientation for the reaction. LD measurements detect DNA bending by the CRP transcription activator protein, as well as by the UvrB DNA repair protein. LD can thus provide information about the structures of protein-DNA complexes under various conditions and in real time.

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Esashi, Fumiko, Vitold E. Galkin, Xiong Yu, Edward H. Egelman, and Stephen C. West. "Stabilization of RAD51 nucleoprotein filaments by the C-terminal region of BRCA2." Nature Structural & Molecular Biology 14, no. 6 (May 21, 2007): 468–74. http://dx.doi.org/10.1038/nsmb1245.

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43

Branzei, D., and M. Foiani. "RecQ helicases queuing with Srs2 to disrupt Rad51 filaments and suppress recombination." Genes & Development 21, no. 23 (December 1, 2007): 3019–26. http://dx.doi.org/10.1101/gad.1624707.

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44

Schay, Gusztáv, Bálint Borka, Linda Kernya, Éva Bulyáki, József Kardos, Melinda Fekete, and Judit Fidy. "Without Binding ATP, Human Rad51 Does Not Form Helical Filaments on ssDNA." Journal of Physical Chemistry B 120, no. 9 (March 2016): 2165–78. http://dx.doi.org/10.1021/acs.jpcb.5b12220.

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45

Zadorozhny, Karina, Vincenzo Sannino, Ondrej Beláň, Jarmila Mlčoušková, Mário Špírek, Vincenzo Costanzo, and Lumír Krejčí. "Fanconi-Anemia-Associated Mutations Destabilize RAD51 Filaments and Impair Replication Fork Protection." Cell Reports 21, no. 2 (October 2017): 333–40. http://dx.doi.org/10.1016/j.celrep.2017.09.062.

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46

Špírek, Mário, Jarmila Mlčoušková, Ondrej Beláň, Máté Gyimesi, Gábor M. Harami, Eszter Molnár, Jiri Novacek, Mihály Kovács, and Lumir Krejci. "Human RAD51 rapidly forms intrinsically dynamic nucleoprotein filaments modulated by nucleotide binding state." Nucleic Acids Research 46, no. 8 (February 22, 2018): 3967–80. http://dx.doi.org/10.1093/nar/gky111.

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47

Crickard, J. Brooks, Kyle Kaniecki, YoungHo Kwon, Patrick Sung, and Eric C. Greene. "Spontaneous self-segregation of Rad51 and Dmc1 DNA recombinases within mixed recombinase filaments." Journal of Biological Chemistry 293, no. 11 (January 30, 2018): 4191–200. http://dx.doi.org/10.1074/jbc.ra117.001143.

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48

van der Heijden, Thijn, Ralf Seidel, Mauro Modesti, Roland Kanaar, Claire Wyman, and Cees Dekker. "Real-time assembly and disassembly of human RAD51 filaments on individual DNA molecules." Nucleic Acids Research 35, no. 17 (August 20, 2007): 5646–57. http://dx.doi.org/10.1093/nar/gkm629.

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49

Day, Melinda, Tyler Maclay, Amber Cyr, Muneer G. Hasham, Kin-hoe Chow, ED Keniston, and Kevin Mills. "Targeting Homologous Recombination in Lymphoid Malignancies: Evaluation of Four Small Molecule Inhibitors of RAD51." Blood 134, Supplement_1 (November 13, 2019): 2080. http://dx.doi.org/10.1182/blood-2019-131747.

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Анотація:

Genomic instability is recognized as a driver of tumorigenesis and cancer progression. Loss of tumor suppressors or activation of oncogenes can induce DNA damage stress, promoting genomic instability and creating dependencies upon key DNA repair pathways. These dependencies can be targeted therapeutically to induce synthetic lethality. The homologous recombination (HR) repair pathway is an attractive target. HR deficient cancers are hypersensitive to numerous anticancer drugs, and tumors will often induce expression of HR genes to promote drug resistance. RAD51 is a key component of the HR pathway. RAD51 forms nucleoprotein filaments at sites of DNA damage and replication fork stalls, mediating homologous DNA strand exchange to promote recombinational repair of breaks and damaged replication forks. We utilized four small molecule inhibitors of RAD51-mediated HR for evaluation of RAD51 as a potential therapeutic target. Compounds CYT-0851, CYT-0853, CYT-1027, and CYT-1127 were evaluated for anti-cancer activity in vitro and in vivo. To determine the impact of the small molecules on RAD51 and HR, all four were tested for effects on RAD51 focus formation and sister chromatid exchange (SCE) activity. All the compounds showed a reduction in SCE activity, however only CYT-0851 and CYT-0853 produced a measurable reduction in RAD51 foci. We have previously shown that that RAD51 inhibition leads to accumulation of DNA breaks, and ultimately cell death, in cells expressing the DNA mutator protein Activation Induced Cytidine deaminase (AICDA/AID). Cytotoxicity assays were performed in an AID+ (Daudi, Burkitt's Lymphoma) and AID- (WI-38, fibroblast) cell lines. All four compounds were preferentially active in AID+ cells with little to no cytotoxicity observed in the AID-negative WI-38 cell line. CYT-0853 was the most potent in the Daudi cell line with an EC50 of 8nM. All four compounds were orally bioavailable in all preclinical species tested but showed differences in pharmacokinetics. Preclinical cell line derived xenograft models of AID-high Burkitt's lymphoma (Daudi) and B-cell acute lymphoblastic leukemia (CCRF-SB) were used to determine the in vivo anti-tumor activity of the compounds in lymphoid cancer models. CYT-0851 and CYT-0853 both showed significant anti-tumor activity with tumor growth inhibition of greater than 50% in both models. Further analysis showed drug exposure with CYT-0851 was more consistent in the CDX models than CYT-0853. Overall, these data indicate that RAD51 and HR are attractive therapeutic targets for the treatment of lymphoid malignancies and that CYT-0851 is a viable clinical development candidate. Disclosures Day: Cyteir Therapeutics: Employment. Maclay:Cyteir Therapeutics: Employment. Cyr:Cyteir Therapeutics: Employment. Mills:Cyteir Therapeutics: Employment, Equity Ownership.

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Andrs, Martin, Zdenka Hasanova, Anna Oravetzova, Jana Dobrovolna, and Pavel Janscak. "RECQ5: A Mysterious Helicase at the Interface of DNA Replication and Transcription." Genes 11, no. 2 (February 21, 2020): 232. http://dx.doi.org/10.3390/genes11020232.

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RECQ5 belongs to the RecQ family of DNA helicases. It is conserved from Drosophila to humans and its deficiency results in genomic instability and cancer susceptibility in mice. Human RECQ5 is known for its ability to regulate homologous recombination by disrupting RAD51 nucleoprotein filaments. It also binds to RNA polymerase II (RNAPII) and negatively regulates transcript elongation by RNAPII. Here, we summarize recent studies implicating RECQ5 in the prevention and resolution of transcription-replication conflicts, a major intrinsic source of genomic instability during cancer development.