"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 . . "1"^^ . "The role of Cdk12 and C-terminal domain of RNA polymerase II in transcription-coupled genome instability"@en . " Cdk9" . "RNA polymer\u00E1za II (RNAPII) \u0159\u00EDd\u00ED transkripci protein k\u00F3duj\u00EDc\u00EDch gen\u016F. Obsahuje C-termin\u00E1ln\u00ED dom\u00E9nu (CTD) s repetic\u00ED heptapeptidu YSPTSPS, kde jsou jednotliv\u00E9 seriny (Ser) fosforylov\u00E1ny. Fosforyla\u010Dn\u00ED status CTD reguluje transkrip\u010Dn\u00ED cyklus a dal\u0161\u00ED bune\u010Dn\u00E9 procesy. N\u00E1\u0161 v\u00FDzkum vedl k objevu role CTD v transkrip\u010Dn\u011B regulovan\u00E9m procesu genomov\u00E9 nestability. Identifikovali jsme Cyklin K-asociovan\u00E9 kin\u00E1zy Cdk12 and Cdk13 a d\u00E1le jsme zjistili, \u017Ee Cdk12 fosforyluje Ser2 v CTD a \u017Ee reguluje expresi v\u00FDznamn\u00FDch \u201CDNA damage response\u201D (DDR) gen\u016F, v\u010Detn\u011B BRCA1, FANCI a ATR. V souladu s t\u00EDmto zji\u0161ten\u00EDm je deregulace proteinu Cdk12 v r\u016Fzn\u00FDch n\u00E1dorech. Nicm\u00E9n\u00E9, mechanismus, kter\u00FD, \u0159\u00EDd\u00ED expresi Cdk12 z\u00E1visl\u00FDch DDR gen\u016F je nejasn\u00FD; podobn\u011B funkce Cdk13 v bunce nen\u00ED zn\u00E1m\u00E1. N\u00E1vrh tohoto grantu m\u00E1 za c\u00EDl: 1) identifikaci proteinov\u00FDch komplex\u016F Cdk12 a Cdk13, 2) zjist\u011Bn\u00ED role Cdk12 regulovan\u00E9 transkrip\u010Dn\u00ED elongace a mRNA procesov\u00E1n\u00ED na expresi DDR genu a 3) objasn\u011Bn\u00ED funkce Ser2 kin\u00E1zov\u00E9 activity Cdk12 pri expresi DDR gen\u016F a p\u0159i vzniku rakoviny." . . " BRCA1" . "2"^^ . "0"^^ . "2"^^ . . "0"^^ . " cancer" . . . . . . . . . . "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\u2026"@en . " DNA damage response" . "Role Cdk12 a C-termin\u00E1ln\u00ED dom\u00E9ny RNA polymer\u00E1zy II v transkripcn\u011B regulovan\u00E9m procesu genomov\u00E9 nestability" . "GA14-09979S" . " P-TEFb" . " transcription" . " FANCI" . "2014-01-01+01:00"^^ . "Cdk12" . "2016-12-31+01:00"^^ . . " genome stability" . "2015-04-23+02:00"^^ . " Cyclin K" . . . . "http://www.isvav.cz/projectDetail.do?rowId=GA14-09979S"^^ . . " C-terminal domain of RNA polymerase II" . " Cdk13" . " phosphorylation of Ser2 in the C-terminal domain of RNA polymerase II" . "2014-03-14+01:00"^^ . " transcriptional elogation" .