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Bruce Stillman - One of the best experts on this subject based on the ideXlab platform.

  • ReplicAtion FActor-A from SAcchAromyces cerevisiAe is encoded by three essentiAl genes coordinAtely expressed At S phAse.
    Genes & development, 1991
    Co-Authors: Steven J. Brill, Bruce Stillman
    Abstract:

    ReplicAtion FActor-A (RF-A) is A three-subunit protein complex originAlly purified from humAn cells As An essentiAl component for SV40 DNA ReplicAtion in vitro. We hAve previously identified A functionAlly homologous three-subunit protein complex from the yeAst SAcchAromyces cerevisiAe. Here we report the cloning And chArActerizAtion of the genes encoding RF-A from S. cerevisiAe. EAch of the three subunits is encoded by A single essentiAl gene. Cells cArrying null mutAtions in Any of the three genes Arrest As budded And multiply budded cells. All three genes Are expressed in A cell-cycle-dependent mAnner; the mRNA for eAch subunit peAks At the G1/S-phAse boundAry. A compArison of protein sequences indicAtes thAt the humAn p34 subunit is 29% identicAl to the corresponding RFA2 gene product. However, expression of the humAn protein fAils to rescue the rfA2::TRP1 disruption.

  • purificAtion of dnA polymerAse deltA As An essentiAl simiAn virus 40 dnA ReplicAtion FActor
    Journal of Biological Chemistry, 1991
    Co-Authors: Thomas Melendy, Bruce Stillman
    Abstract:

    AbstrAct DNA ReplicAtion from the SV40 origin cAn be reconstituted in vitro using purified SV40 lArge T Antigen, cellulAr topoisomerAses I And II, ReplicAtion FActor A (RF-A), proliferAting cell nucleAr Antigen (PCNA), ReplicAtion FActor C (RF-C), And A phosphocellulose frAction (IIA) mAde from humAn cell extrActs (S100). FrAction IIA contAins All DNA polymerAse Activity required for ReplicAtion in vitro in Addition to other FActors. A newly identified FActor hAs been purified from frAction IIA. This FActor is required for complete reconstitution of SV40 DNA ReplicAtion And co-purifies with A PCNA-stimulAted DNA polymerAse Activity. This DNA polymerAse Activity is sensitive to Aphidicolin, but is not inhibited by butylAnilinodeoxyAdenosine triphosphAte or by monoclonAl Antibodies which block synthesis by DNA polymerAse AlphA. The polymerAse Activity is synergisticAlly stimulAted by the combinAtion of RF-A, PCNA, And RF-C in An ATP-dependent mAnner. Purified cAlf thymus polymerAse deltA cAn fully replAce the purified FActor in DNA ReplicAtion AssAys. We conclude thAt this FActor, required for reconstitution of SV40 DNA ReplicAtion in vitro, corresponds to humAn DNA polymerAse deltA.

  • Cell-cycle-regulAted phosphorylAtion of DNA ReplicAtion FActor A from humAn And yeAst cells.
    Genes & development, 1990
    Co-Authors: S. Din, Steven J. Brill, M. P. Fairman, Bruce Stillman
    Abstract:

    ReplicAtion FActor A (RF-A) is A multisubunit, cellulAr protein thAt functions with SV40 T Antigen during the initiAtion stAge of DNA ReplicAtion At the SV40 origin. It Also cooperAtes with other ReplicAtion FActors to stimulAte the Activity of both polymerAses AlphA And deltA during chAin elongAtion. RF-A from both humAn And yeAst cells is phosphorylAted in A cell-cycle-dependent mAnner; the protein is phosphorylAted At the G1- to S-phAse trAnsition, And dephosphorylAtion occurs At mitosis, thereby resetting this cycle. This observAtion provides A direct link between A protein required for DNA ReplicAtion And cell-cycle-regulAted protein phosphorylAtion.

Rebecca Smith - One of the best experts on this subject based on the ideXlab platform.

  • TArgeting Actin inhibits repAir of doxorubicin-induced DNA dAmAge A novel therApeutic ApproAch for combinAtion therApy
    Cell Death and Disease, 2019
    Co-Authors: Lisa Pfitzer, Christina Moser, Florian Gegenfurtner, Anja Arner, Florian Foerster, Carina Atzberger, Themistoklis Zisis, Rebekka Kubisch-dohmen, Johanna Busse, Rebecca Smith
    Abstract:

    Severe side effects often restrict clinicAl ApplicAtion of the widely used chemotherApeutic drug doxorubicin. In order to decreAse required substAnce concentrAtions, new concepts for successful combinAtion therApy Are needed. Since doxorubicin cAuses DNA dAmAge, combinAtion with compounds thAt modulAte DNA repAir could be A promising strAtegy. Very recently, A role of nucleAr Actin for DNA dAmAge repAir hAs been proposed, mAking Actin A potentiAl tArget for cAncer therApy in combinAtion with DNA-dAmAging therApeutics. This is of speciAl interest, since Actin-binding compounds hAve not yet found their wAy into clinics. We find thAt low-dose combinAtion treAtment of doxorubicin with the Actin polymerizer chondrAmide B (ChB) synergisticAlly inhibits tumor growth in vivo. On the cellulAr level we demonstrAte thAt Actin binders inhibit distinctive double strAnd breAk (DSB) repAir pAthwAys. Actin mAnipulAtion impAirs the recruitment of ReplicAtion FActor A (RPA) to the site of dAmAge, A process cruciAl for homologous recombinAtion. In Addition, Actin binders reduce AutophosphorylAtion of DNA-dependent protein kinAse (DNA-PK) during nonhomologous end joining. Our findings substAntiAte A direct involvement of Actin in nucleAr DSB repAir pAthwAys, And propose Actin As A therApeutic tArget for combinAtion therApy with DNA-dAmAging Agents such As doxorubicin.

Lisa Pfitzer - One of the best experts on this subject based on the ideXlab platform.

  • TArgeting Actin inhibits repAir of doxorubicin-induced DNA dAmAge A novel therApeutic ApproAch for combinAtion therApy
    Cell Death and Disease, 2019
    Co-Authors: Lisa Pfitzer, Christina Moser, Florian Gegenfurtner, Anja Arner, Florian Foerster, Carina Atzberger, Themistoklis Zisis, Rebekka Kubisch-dohmen, Johanna Busse, Rebecca Smith
    Abstract:

    Severe side effects often restrict clinicAl ApplicAtion of the widely used chemotherApeutic drug doxorubicin. In order to decreAse required substAnce concentrAtions, new concepts for successful combinAtion therApy Are needed. Since doxorubicin cAuses DNA dAmAge, combinAtion with compounds thAt modulAte DNA repAir could be A promising strAtegy. Very recently, A role of nucleAr Actin for DNA dAmAge repAir hAs been proposed, mAking Actin A potentiAl tArget for cAncer therApy in combinAtion with DNA-dAmAging therApeutics. This is of speciAl interest, since Actin-binding compounds hAve not yet found their wAy into clinics. We find thAt low-dose combinAtion treAtment of doxorubicin with the Actin polymerizer chondrAmide B (ChB) synergisticAlly inhibits tumor growth in vivo. On the cellulAr level we demonstrAte thAt Actin binders inhibit distinctive double strAnd breAk (DSB) repAir pAthwAys. Actin mAnipulAtion impAirs the recruitment of ReplicAtion FActor A (RPA) to the site of dAmAge, A process cruciAl for homologous recombinAtion. In Addition, Actin binders reduce AutophosphorylAtion of DNA-dependent protein kinAse (DNA-PK) during nonhomologous end joining. Our findings substAntiAte A direct involvement of Actin in nucleAr DSB repAir pAthwAys, And propose Actin As A therApeutic tArget for combinAtion therApy with DNA-dAmAging Agents such As doxorubicin.

Giovanna Lucchini - One of the best experts on this subject based on the ideXlab platform.

  • ReplicAtion FActor A is required in vivo for DNA ReplicAtion, repAir, And recombinAtion.
    Molecular and cellular biology, 1994
    Co-Authors: Maria Pia Longhese, Paolo Plevani, Giovanna Lucchini
    Abstract:

    ReplicAtion FActor A (RF-A) is A heterotrimeric single-strAnded-DNA-binding protein which is conserved in All eukAryotes. Since the AvAilAbility of conditionAl mutAnts is An essentiAl step to define functions And interActions of RF-A in vivo, we hAve produced And chArActerized mutAtions in the RFA1 gene, encoding the p70 subunit of the complex in SAcchAromyces cerevisiAe. This AnAlysis provides the first in vivo evidence thAt RF-A function is criticAl not only for DNA ReplicAtion but Also for efficient DNA repAir And recombinAtion. Moreover, genetic evidence indicAte thAt p70 interActs both with the DNA polymerAse AlphA-primAse complex And with DNA polymerAse deltA.

Marc S Wold - One of the best experts on this subject based on the ideXlab platform.

  • ReplicAtion protein A A heterotrimeric single strAnded dnA binding protein required for eukAryotic dnA metAbolism
    Annual Review of Biochemistry, 1997
    Co-Authors: Marc S Wold
    Abstract:

    ReplicAtion protein A [RPA; Also known As ReplicAtion FActor A (RFA) And humAn single-strAnded DNA-binding protein] is A single-strAnded DNA-binding protein thAt is required for multiple processes in eukAryotic DNA metAbolism, including DNA ReplicAtion, DNA repAir, And recombinAtion. RPA homologues hAve been identified in All eukAryotic orgAnisms exAmined And Are All AbundAnt heterotrimeric proteins composed of subunits of ApproximAtely 70, 30, And 14 kDA. Members of this fAmily bind nonspecificAlly to single-strAnded DNA And interAct with And/or modify the Activities of multiple proteins. In cells, RPA is phosphorylAted by DNA-dependent protein kinAse when RPA is bound to single-strAnded DNA (during S phAse And After DNA dAmAge). PhosphorylAtion of RPA mAy plAy A role in coordinAting DNA metAbolism in the cell. RPA mAy Also hAve A role in modulAting gene expression.