Polo - like kinase - 1 is a target of the DNA damage checkpoint

  • Smits V
  • Klompmaker R
  • Arnaud L
 et al. 
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Abstract

See, stats, and : https : / / www . researchgate . net / publication / 12340987 Polo -like - 1 damage Article DOI : 10 . 1038 / 35023629 : PubMed CITATIONS 363 READS 80 6 , including : Some : TLK2 drug Lionel Institut , … 34 , 135 SEE Erich University 393 , 329 SEE René Netherlands 392 , 631 SEE All . The . Polo - like kinases (PLKs) have an important role in sever - al stages of mitosis . They contribute to the activation of cyclin B / Cdc2 and are involved in centrosome maturation and bipolar spindle formation at the onset of mitosis 1 , 2 . PLKs also control mitotic exit by regulating the anaphase - promoting complex (APC) and have been implicated in the temporal and spatial coordination of cytokinesis 1 , 2 . Experiments in budding yeast have shown that the PLK Cdc5 may be controlled by the DNA damage check - point 3 ,4.HerewereporttheeffectsofDNAdamageonPolo-likekinase-1(Plk1)inavarietyofhumancelllines.WeshowthatPlk1isinhibitedbyDNAdamageinG2andinmitosis.Inlinewiththis,weshowthatDNAdamageblocksmitoticexit.DNAdamagedoesnotinhibitthekinaseactivityofPlk1mutantsinwhichtheconservedthreonineresidueintheT-loophasbeenchangedtoasparticacid,suggestingthatDNAdamageinterfereswiththeactivationofPlk1.Significantly,expressionofthesemutantscanoverridetheG2arrestinducedbyDNAdamage.OnthebasisofthesedataweproposethatPlk1isanimportanttargetoftheDNAdamagecheckpoint,enablingcell-cyclearrestsatmultiplepointsinG2andmitosis.CheckpointactivationbyDNAdamageduringG2preventsactivationofcyclinB/Cdc2complexesbytheCdc25Cphos-phatase,andasaconsequencemitoticentryisblocked5.InhibitionofCdc25CcanbemediatedbytheDNAdamage-acti-vatedkinasesChk1/Cds1,resultinginnuclearexclusion6,anddirectinhibitionofCdc25Ccatalyticactivity7.Inaddition,Cdc25Cacti-vationrequirespositiveregulatoryphosphorylation,whichcanbeestablishedbycyclinB/Cdc2complexes8,9,orbyincubationwithPLKs10,11.Infact,inXenopus,depletionofthepolo-likekinasePlx1causesablockinCdc25C-activation,whichsuggeststhatPLKspro-videtheinitialtriggerforCdc25Cactivation11.Severallinesofevi-denceindicatethatCdc5,thepolo-likekinaseinbuddingyeast,iscontrolledbytheDNAdamagecheckpoint.Cdc5ismodifiedinresponsetoDNAdamageinaRad53-dependentmanner3

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Authors

  • Veronique A J Smits

  • Rob Klompmaker

  • Lionel Arnaud

  • Gert Rijksen

  • Erich A Nigg

  • René H Medema

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