Putting together and taking apart: assembly and disassembly of the Rad51 nucleoprotein filament in DNA repair and genome stability

Andriuskevicius, Tadas; Kotenko, Oleksii; Makovets, Svetlana

doi:10.15698/cst2018.05.134

Cited by 16 publications

(24 citation statements)

References 189 publications

(285 reference statements)

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“…RAD51 binding to ssDNA, and consequently the assembly and disassembly of the RAD51 filament, is dependent on RAD51 binding, the RAD51 protein levels and the activity of both positive and negative regulators of HR. Underscoring the importance of tightly controlling RAD51 activity, upregulation or downregulation is associated with genome instability and cancer ( 8 , 40 ).…”

Section: Rad51 and Genome Stabilitymentioning

confidence: 99%

Regulation and pharmacological targeting of RAD51 in cancer

2020

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Regulation of homologous recombination (HR) is central for cancer prevention. However, too little HR can increase cancer incidence, whereas too much HR can drive cancer resistance to therapy. Importantly, therapeutics targeting HR deficiency have demonstrated a profound efficacy in the clinic improving patient outcomes, particularly for breast and ovarian cancer. RAD51 is central to DNA damage repair in the HR pathway. As such, understanding the function and regulation of RAD51 is essential for cancer biology. This review will focus on the role of RAD51 in cancer and beyond and how modulation of its function can be exploited as a cancer therapeutic.

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Section: Rad51 and Genome Stabilitymentioning

confidence: 99%

Regulation and pharmacological targeting of RAD51 in cancer

2020

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“…Biochemical studies with eukaryotic proteins demonstrated that the ssDNA binding protein RPA, if added to the partially formed nucleoprotein filament, promotes the fully assembled Rad51 filament (reviewed in [56,69]). When added before Rad51, RPA binding affinity to ssDNA usually inhibits filament formation of Rad51 and Rad52 is required as a mediator on this RPA-coated ssDNA.…”

Section: Rada Catalyzes D-loop Formation On a Circular Dna Substratementioning

confidence: 99%

Role of RadA and DNA Polymerases in Recombination-Associated DNA Synthesis in Hyperthermophilic Archaea

et al. 2020

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Among the three domains of life, the process of homologous recombination (HR) plays a central role in the repair of double-strand DNA breaks and the restart of stalled replication forks. Curiously, main protein actors involved in the HR process appear to be essential for hyperthermophilic Archaea raising interesting questions about the role of HR in replication and repair strategies of those Archaea living in extreme conditions. One key actor of this process is the recombinase RadA, which allows the homologous strand search and provides a DNA substrate required for following DNA synthesis and restoring genetic information. DNA polymerase operation after the strand exchange step is unclear in Archaea. Working with Pyrococcus abyssi proteins, here we show that both DNA polymerases, family-B polymerase (PolB) and family-D polymerase (PolD), can take charge of processing the RadA-mediated recombination intermediates. Our results also indicate that PolD is far less efficient, as compared with PolB, to extend the invaded DNA at the displacement-loop (D-loop) substrate. These observations coincide with previous genetic analyses obtained on Thermococcus species showing that PolB is mainly involved in DNA repair without being essential probably because PolD could take over combined with additional partners.

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“…HR, which is generally considered to be an error-free process, may be an important source of genomic instability due to rearrangements between the invading and homologous strands with repetitive regions, formation of hairpins during D-loop extension, and difficulties associated with synthesis across repetitive regions, especially those that form DNA secondary structures [27,140–142]. The most important recombination proteins are Rad52 and Rad51 [96,98,143]. Deletion of RAD52 or RAD51 reduced the instability of repeat tracts compared to the psf1-1 mutant (Fig 5B–5D) what supports the conclusion that HR mechanisms are involved in this process (Fig 5F–5H).…”

Section: Discussionmentioning

confidence: 99%

Defects in the GINS complex increase the instability of repetitive sequences via a recombination-dependent mechanism

et al. 2019

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Faithful replication and repair of DNA lesions ensure genome maintenance. During replication in eukaryotic cells, DNA is unwound by the CMG helicase complex, which is composed of three major components: the Cdc45 protein, Mcm2-7, and the GINS complex. The CMG in complex with DNA polymerase epsilon (CMG-E) participates in the establishment and progression of the replisome. Impaired functioning of the CMG-E was shown to induce genomic instability and promote the development of various diseases. Therefore, CMG-E components play important roles as caretakers of the genome. In Saccharomyces cerevisiae, the GINS complex is composed of the Psf1, Psf2, Psf3, and Sld5 essential subunits. The Psf1-1 mutant form fails to interact with Psf3, resulting in impaired replisome assembly and chromosome replication. Here, we show increased instability of repeat tracts (mononucleotide, dinucleotide, trinucleotide and longer) in yeast psf1-1 mutants. To identify the mechanisms underlying this effect, we analyzed repeated sequence instability using derivatives of psf1-1 strains lacking genes involved in translesion synthesis, recombination, or mismatch repair. Among these derivatives, deletion of RAD52, RAD51, MMS2, POL32, or PIF1 significantly decreased DNA repeat instability. These results, together with the observed increased amounts of single-stranded DNA regions and Rfa1 foci suggest that recombinational mechanisms make important contributions to repeat tract instability in psf1-1 cells. We propose that defective functioning of the CMG-E complex in psf1-1 cells impairs the progression of DNA replication what increases the contribution of repair mechanisms such as template switch and break-induced replication. These processes require sequence homology search which in case of a repeated DNA tract may result in misalignment leading to its expansion or contraction.

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Putting together and taking apart: assembly and disassembly of the Rad51 nucleoprotein filament in DNA repair and genome stability

Cited by 16 publications

References 189 publications

Regulation and pharmacological targeting of RAD51 in cancer

Regulation and pharmacological targeting of RAD51 in cancer

Role of RadA and DNA Polymerases in Recombination-Associated DNA Synthesis in Hyperthermophilic Archaea

Defects in the GINS complex increase the instability of repetitive sequences via a recombination-dependent mechanism

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