Replication protein A as a major eukaryotic single-stranded DNA-binding protein and its role in DNA repair

Krasikova, Y. S.; Rechkunova, N. I.; Lavrik, Olga I.

doi:10.1134/s0026893316030080

Cited by 11 publications

(15 citation statements)

References 133 publications

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“…Both RPA and XPA are indispensable NER factors required for repair process in vivo and in vitro [ 15 , 50 ]. In the present study, we found that XPA binds to DNA mimicking post-incision intermediates with less affinity than to bubble-DNA intermediate ( Fig 4C ) whereas RPA has some preference for DNA mimicking NER intermediates formed after the action of XPF-ERCC1.…”

Section: Discussionmentioning

confidence: 99%

“…RPA, an evolutionarily conserved heterotrimeric protein, binds and stabilizes ssDNA regions appearing in various cellular events [ 14 , 15 ]. In NER, RPA plays an integral role in damage recognition preceding the incision of the damage, and then again in post-excision DNA repair synthesis.…”

Section: Discussionmentioning

confidence: 99%

“…RPA, the major eukaryotic ssDNA-binding protein, is essential for DNA replication, recombination, repair, and DNA damage checkpoint. Each of the RPA subunits (70, 32 and 14 kDa) contains one or more DNA-binding domains (DBD) [ 14 , 15 ] that cause RPA to possess multiple modes of DNA binding that differ in the amount of nucleotide residues occluded by the protein and in the number of domains interacting with the DNA [ 16 – 18 ]. RPA binds ssDNA with high affinity [ 19 , 20 ] and it also binds to damaged dsDNA with some degree of specificity [ 21 – 23 ].…”

Section: Introductionmentioning

confidence: 99%

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RPA and XPA interaction with DNA structures mimicking intermediates of the late stages in nucleotide excision repair

et al. 2018

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Replication protein A (RPA) and the xeroderma pigmentosum group A (XPA) protein are indispensable for both pathways of nucleotide excision repair (NER). Here we analyze the interaction of RPA and XPA with DNA containing a flap and different size gaps that imitate intermediates of the late NER stages. Using gel mobility shift assays, we found that RPA affinity for DNA decreased when DNA contained both extended gap and similar sized flap in comparison with gapped-DNA structure. Moreover, crosslinking experiments with the flap-gap DNA revealed that RPA interacts mainly with the ssDNA platform within the long gap and contacts flap in DNA with a short gap. XPA exhibits higher affinity for bubble-DNA structures than to flap-gap-containing DNA. Protein titration analysis showed that formation of the RPA-XPA-DNA ternary complex depends on the protein concentration ratio and these proteins can function as independent players or in tandem. Using fluorescently-labelled RPA, direct interaction of this protein with XPA was detected and characterized quantitatively. The data obtained allow us to suggest that XPA can be involved in the post-incision NER stages via its interaction with RPA.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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RPA and XPA interaction with DNA structures mimicking intermediates of the late stages in nucleotide excision repair

et al. 2018

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“…To explore the blockade of DSB repair in miR-1193/ FEN1-deficient cells, we investigated the ssDNA repair intermediates generated by DNA end resection during the induction of pre-apoptosis in miR-1193/FEN1-depleted cells. The presence of nuclear RPA foci, a marker of ssDNA repair intermediates 44 , was assessed by an immunofluorescence assay in both M059J and M059K cells transfected with anti-miR-1193 or anti-miR-NC. In contrast to M059K cells, M059J cells transfected with anti-miR-1193 exhibited compelling accumulation of RPA foci ( Fig.…”

Section: Anti-mir-1193 Increases Dsb Damage In M059j Cells With Dna-pmentioning

confidence: 99%

Inhibition of miR-1193 leads to synthetic lethality in glioblastoma multiforme cells deficient of DNA-PKcs

Zhang

Tan

et al. 2020

Cell Death Dis

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Glioblastoma multiforme (GBM) is the most malignant primary brain tumor and has the highest mortality rate among cancers and high resistance to radiation and cytotoxic chemotherapy. Although some targeted therapies can partially inhibit oncogenic mutation-driven proliferation of GBM cells, therapies harnessing synthetic lethality are ‘coincidental’ treatments with high effectiveness in cancers with gene mutations, such as GBM, which frequently exhibits DNA-PKcs mutation. By implementing a highly efficient high-throughput screening (HTS) platform using an in-house-constructed genome-wide human microRNA inhibitor library, we demonstrated that miR-1193 inhibition sensitized GBM tumor cells with DNA-PKcs deficiency. Furthermore, we found that miR-1193 directly targets YY1AP1, leading to subsequent inhibition of FEN1, an important factor in DNA damage repair. Inhibition of miR-1193 resulted in accumulation of DNA double-strand breaks and thus increased genomic instability. RPA-coated ssDNA structures enhanced ATR checkpoint kinase activity, subsequently activating the CHK1/p53/apoptosis axis. These data provide a preclinical theory for the application of miR-1193 inhibition as a potential synthetic lethal approach targeting GBM cancer cells with DNA-PKcs deficiency.

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“…Because of its central role in virtually all aspects of cellular DNA metabolism, a number of authoritative reviews (3,37,(42)(43)(44)(45)(46) paralleled the development of the models for the regulation of the RPA-ssDNA interaction and the mechanisms underlying the handoff of ssDNA from RPA to correct ssDNA binding/processing proteins with functions in DNA replication, repair and homologous recombination. Recent single-molecule and structural studies (36,(38)(39)(40)(41)47,48) allow us to update the existing models.…”

Section: Introductionmentioning

confidence: 99%

Dynamic elements of replication protein A at the crossroads of DNA replication, recombination, and repair

Caldwell

Spies

2020

Critical Reviews in Biochemistry and Molecular Biology

102

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The heterotrimeric eukaryotic Replication protein A (RPA) is a master regulator of numerous DNA metabolic processes. For a long time it has been viewed as an inert protector of ssDNA and a platform for assembly of various genome maintenance and signaling machines. Later, modular organization of the RPA DNA binding domains suggested a possibility for a dynamic interaction with ssDNA. This modular organization has inspired several models for the RPA-ssDNA interaction that aimed to explain how RPA, the high affinity ssDNA binding protein, is replaced by the downstream players in DNA replication, recombination and repair that bind ssDNA with much lower affinity. Recent studies, and in particular single-molecule observations of RPA-ssDNA interactions, led to the development of a new model for the ssDNA handoff from RPA to a specific downstream factor where not only stability and structural rearrangements, but also RPA conformational dynamics guide the ssDNA handoff. Here we will review the current knowledge of the RPA structure, its dynamic interaction with ssDNA, and how RPA conformational dynamics may be influenced by posttranslational modification and proteins that interact with RPA, as well as how RPA dynamics may be harnessed in cellular decision making.

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Replication protein A as a major eukaryotic single-stranded DNA-binding protein and its role in DNA repair

Cited by 11 publications

References 133 publications

RPA and XPA interaction with DNA structures mimicking intermediates of the late stages in nucleotide excision repair

RPA and XPA interaction with DNA structures mimicking intermediates of the late stages in nucleotide excision repair

Inhibition of miR-1193 leads to synthetic lethality in glioblastoma multiforme cells deficient of DNA-PKcs

Dynamic elements of replication protein A at the crossroads of DNA replication, recombination, and repair

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