CDK12 kinase activity controls G1/S progression by regulating
optimal transcription of core DNA replication genes

a 2018

CDK12 kinase activity controls G1/S progression by regulating optimal transcription of core DNA replication genes

CHIRACKAL MANAVALAN, Anil Paul, Květa PILAŘOVÁ, M. KLUGE, Koen BARTHOLOMEEUSEN, Jan OPPELT et. al.

Základní údaje

Originální název

CDK12 kinase activity controls G1/S progression by regulating optimal transcription of core DNA replication genes

Autoři

CHIRACKAL MANAVALAN, Anil Paul (356 Indie, domácí), Květa PILAŘOVÁ (203 Česká republika, domácí), M. KLUGE (276 Německo), Koen BARTHOLOMEEUSEN (56 Belgie, domácí), Jan OPPELT (203 Česká republika, domácí), PrashantKumar KHIRSARIYA (356 Indie, domácí), Kamil PARUCH (203 Česká republika, domácí), Lumír KREJČÍ (203 Česká republika, domácí), C. FRIEDEL (276 Německo) a Dalibor BLAŽEK (203 Česká republika, garant, domácí)

Vydání

2018 ASCB | EMBO Annual Meeting, 2018

Další údaje

Jazyk

angličtina

Typ výsledku

Konferenční abstrakt

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Kód RIV

RIV/00216224:14740/18:00106752

Organizační jednotka

Středoevropský technologický institut

Klíčová slova anglicky

CDK12kinase; DNA replication genes

Štítky

rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 3. 4. 2019 10:55, Mgr. Pavla Foltynová, Ph.D.

Anotace

V originále

Cyclin dependent kinase 12 (CDK12) is involved in RNA Polymerase II (RNAPII) mediated transcription and its kinase domain is frequently mutated in ovarian, breast and prostate cancers. CDK12 depletion leads to a reduction of phosphorylation of serine 2 (P Ser2) in the C terminal domain (CTD) of RNAPII. We have previously reported that CDK12 regulates the transcription of homologous recombination (HR) DNA repair genes. However, comprehensive insight into its target genes and cellular processes remains largely obscure mainly because of the lack of tools to specifically inhibit CDK12. Therefore we generated cells carrying analog sensitive alleles of CDK12 and studied CDK12 catalytic activity in dynamic processes of transcription and cell cycle progression. We show that CDK12 is mostly expressed in G1 phase and its kinase activity is required for optimal G1/S progression. Moreover, the expression of many DNA replication and repair genes are affected upon CDK12 inhibition. To investigate further, we carried out nuclear RNA seq coupled with ChIP seq for RNAPII, P Ser2 RNAPII and P Ser5 RNAPII and revealed that CDK12 inhibition triggered an RNAPII processivity defect, predominantly at relatively long, poly(A) signal rich genes. Thus, CDK12 kinase activity represents a novel link between regulation of transcription and cell cycle progression. We propose that DNA replication and HR DNA repair defects underlie the CDK12 specific genome instability phenotype observed in many cancers.

Návaznosti

LQ1601, projekt VaV

Název: CEITEC 2020 (Akronym: CEITEC2020)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, CEITEC 2020

Citovat

CHIRACKAL MANAVALAN, Anil Paul, Květa PILAŘOVÁ, M. KLUGE, Koen BARTHOLOMEEUSEN, Jan OPPELT, PrashantKumar KHIRSARIYA, Kamil PARUCH, Lumír KREJČÍ, C. FRIEDEL a Dalibor BLAŽEK. CDK12 kinase activity controls G1/S progression by regulating optimal transcription of core DNA replication genes. In 2018 ASCB | EMBO Annual Meeting. 2018.

@proceedings{1514997,
   author = {Chirackal Manavalan, Anil Paul and Pilařová, Květa and Kluge, M. and Bartholomeeusen, Koen and Oppelt, Jan and Khirsariya, PrashantKumar and Paruch, Kamil and Krejčí, Lumír and Friedel, C. and Blažek, Dalibor},
   booktitle = {2018 ASCB | EMBO Annual Meeting},
   keywords = {CDK12kinase; DNA replication genes},
   language = {eng},
   title = {CDK12 kinase activity controls G1/S progression by regulating optimal transcription of core DNA replication genes},
   year = {2018}
}

TY  - CONF
ID  - 1514997
AU  - Chirackal Manavalan, Anil Paul - Pilařová, Květa - Kluge, M. - Bartholomeeusen, Koen - Oppelt, Jan - Khirsariya, PrashantKumar - Paruch, Kamil - Krejčí, Lumír - Friedel, C. - Blažek, Dalibor
PY  - 2018
TI  - CDK12 kinase activity controls G1/S progression by regulating optimal transcription of core DNA replication genes
KW  - CDK12kinase
KW  - DNA replication genes
N2  - Cyclin dependent kinase 12 (CDK12) is involved in RNA Polymerase II (RNAPII) mediated transcription and its kinase domain is frequently mutated in ovarian, breast and prostate cancers. CDK12 depletion leads to a reduction of phosphorylation of serine 2 (P Ser2) in the C terminal domain (CTD) of RNAPII. We have previously reported that CDK12 regulates the transcription of homologous recombination (HR) DNA repair genes. However, comprehensive insight into its target genes and cellular processes remains largely obscure mainly because of the lack of tools to specifically inhibit CDK12. Therefore we generated cells carrying analog sensitive alleles of CDK12 and studied CDK12 catalytic activity in dynamic processes of transcription and cell cycle progression. We show that CDK12 is mostly expressed in G1 phase and its kinase activity is required for optimal G1/S progression. Moreover, the expression of many DNA replication and repair genes are affected upon CDK12 inhibition. To investigate further, we carried out nuclear RNA seq coupled with ChIP seq for RNAPII, P Ser2 RNAPII and P Ser5 RNAPII and revealed that CDK12 inhibition triggered an RNAPII processivity defect, predominantly at relatively long, poly(A) signal rich genes. Thus, CDK12 kinase activity represents a novel link between regulation of transcription and cell cycle progression. We propose that DNA replication and HR DNA repair defects underlie the CDK12 specific genome instability phenotype observed in many cancers.
ER  -

Podrobný výpis o publikaci