About: The role of Cdk12 and C-terminal domain of RNA polymerase II in transcription-coupled genome instability     Goto   Sponge   NotDistinct   Permalink

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Description
  • RNA polymeráza II (RNAPII) řídí transkripci protein kódujících genů. Obsahuje C-terminální doménu (CTD) s repeticí heptapeptidu YSPTSPS, kde jsou jednotlivé seriny (Ser) fosforylovány. Fosforylační status CTD reguluje transkripční cyklus a další bunečné procesy. Náš výzkum vedl k objevu role CTD v transkripčně regulovaném procesu genomové nestability. Identifikovali jsme Cyklin K-asociované kinázy Cdk12 and Cdk13 a dále jsme zjistili, že Cdk12 fosforyluje Ser2 v CTD a že reguluje expresi významných “DNA damage response” (DDR) genů, včetně BRCA1, FANCI a ATR. V souladu s tímto zjištením je deregulace proteinu Cdk12 v různých nádorech. Nicméné, mechanismus, který, řídí expresi Cdk12 závislých DDR genů je nejasný; podobně funkce Cdk13 v bunce není známá. Návrh tohoto grantu má za cíl: 1) identifikaci proteinových komplexů Cdk12 a Cdk13, 2) zjistění role Cdk12 regulované transkripční elongace a mRNA procesování na expresi DDR genu a 3) objasnění funkce Ser2 kinázové activity Cdk12 pri expresi DDR genů a při vzniku rakoviny.
  • RNA polymerase II (RNAPII) directs transcription of protein-coding genes. It contains a C-terminal domain (CTD) with repeats of heptapeptide YSPTSPS where individual serines (Ser) get phosphorylated. The phosphorylation status of the CTD regulates transcription cycle and other cellular functions. Our study implicated the CTD to have a role in transcription-coupled genome instability. We identified Cyclin K-associated kinases Cdk12 and Cdk13 and found out that Cdk12 phosphorylates Ser2 in the CTD and regulates expression of DNA damage response (DDR) genes including BRCA1, FANCI and ATR. Consistently, Cdk12 is deregulated in tumors. However, the mechanism that directs expression of the Cdk12-dependent DDR genes is unknown; likewise the cellular function of Cdk13 is enigmatic. This proposal aims to: 1) identify Cdk12 and Cdk13 protein complexes, 2) investigate the role of Cdk12-dependent transcriptional elongation and mRNA processing in the expression of DDR genes and 3) clarify the role of the Ser2 kinase activity of Cdk12 in the expression of DDR genes and in the onset of cancer. (en)
Title
  • The role of Cdk12 and C-terminal domain of RNA polymerase II in transcription-coupled genome instability (en)
  • Role Cdk12 a C-terminální domény RNA polymerázy II v transkripcně regulovaném procesu genomové nestability
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  • GA14-09979S
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  • Cdk12, Cdk13, Cyclin K, Cdk9, P-TEFb, transcription, C-terminal domain of RNA polymerase II, phosphorylation of Ser2 in the C-terminal domain of RNA polymerase II, transcriptional elogation, BRCA1, FANCI, DNA damage response, genome stability, cancer, o… (en)
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  • BRCA1
  • C-terminal domain of RNA polymerase II
  • Cdk13
  • Cdk9
  • Cyclin K
  • DNA damage response
  • FANCI
  • P-TEFb
  • cancer
  • genome stability
  • transcription
  • transcriptional elogation
  • phosphorylation of Ser2 in the C-terminal domain of RNA polymerase II
  • Cdk12
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