BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors

J 2017

BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors

PACULOVÁ, Hana, Juraj KRAMARA, Šárka ŠIMEČKOVÁ, Radek FEDR, Karel SOUČEK et. al.

Základní údaje

Originální název

BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors

Autoři

PACULOVÁ, Hana (203 Česká republika), Juraj KRAMARA (703 Slovensko), Šárka ŠIMEČKOVÁ (203 Česká republika, domácí), Radek FEDR (203 Česká republika), Karel SOUČEK (203 Česká republika, domácí), Ondřej HYLSE (203 Česká republika, domácí), Kamil PARUCH (203 Česká republika, garant, domácí), Marek SVOBODA (203 Česká republika), Martin MISTRÍK (203 Česká republika) a Jiří KOHOUTEK (203 Česká republika)

Vydání

Tumor Biology, Springer Netherlands, 2017, 1010-4283

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10401 Organic chemistry

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 3.650 v roce 2016

Kód RIV

RIV/00216224:14310/17:00097945

Organizační jednotka

Přírodovědecká fakulta

DOI

http://dx.doi.org/10.1177/1010428317727479

Klíčová slova anglicky

DNA damage response; BRCA1; CDK12; CHK1 inhibitor; transcription

Štítky

NZ, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 11. 3. 2021 15:15, Mgr. Marie Šípková, DiS.

Anotace

V originále

A broad spectrum of tumors develop resistance to classic chemotherapy, necessitating the discovery of new therapies. One successful strategy exploits the synthetic lethality between poly(ADP-ribose) polymerase 1/2 proteins and DNA damage response genes, including BRCA1, a factor involved in homologous recombination–mediated DNA repair, and CDK12, a transcriptional kinase known to regulate the expression of DDR genes. CHK1 inhibitors have been shown to enhance the anti-cancer effect of DNA-damaging compounds. Since loss of BRCA1 increases replication stress and leads to DNA damage, we tested a hypothesis that CDK12- or BRCA1-depleted cells rely extensively on S-phase-related CHK1 functions for survival. The silencing of BRCA1 or CDK12 sensitized tumor cells to CHK1 inhibitors in vitro and in vivo. BRCA1 downregulation combined with CHK1 inhibition induced excessive amounts of DNA damage, resulting in an inability to complete the S-phase. Therefore, we suggest CHK1 inhibition as a strategy for targeting BRCA1- or CDK12-deficient tumors.

Návaznosti

LM2015063, projekt VaV

Název: Národní infrastruktura chemické biologie (Akronym: CZ-OPENSCREEN)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, CZ-OPENSCREEN: National Infrastructure for Chemical Biology

Citovat

PACULOVÁ, Hana, Juraj KRAMARA, Šárka ŠIMEČKOVÁ, Radek FEDR, Karel SOUČEK, Ondřej HYLSE, Kamil PARUCH, Marek SVOBODA, Martin MISTRÍK a Jiří KOHOUTEK. BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors. Tumor Biology. Springer Netherlands, 2017, roč. 2017, October, s. 1-11. ISSN 1010-4283. Dostupné z: https://dx.doi.org/10.1177/1010428317727479.

@article{1392816,
   author = {Paculová, Hana and Kramara, Juraj and Šimečková, Šárka and Fedr, Radek and Souček, Karel and Hylse, Ondřej and Paruch, Kamil and Svoboda, Marek and Mistrík, Martin and Kohoutek, Jiří},
   article_number = {October},
   doi = {http://dx.doi.org/10.1177/1010428317727479},
   keywords = {DNA damage response; BRCA1; CDK12; CHK1 inhibitor; transcription},
   language = {eng},
   issn = {1010-4283},
   journal = {Tumor Biology},
   title = {BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors},
   url = {https://doi.org/10.1177/1010428317727479},
   volume = {2017},
   year = {2017}
}

TY  - JOUR
ID  - 1392816
AU  - Paculová, Hana - Kramara, Juraj - Šimečková, Šárka - Fedr, Radek - Souček, Karel - Hylse, Ondřej - Paruch, Kamil - Svoboda, Marek - Mistrík, Martin - Kohoutek, Jiří
PY  - 2017
TI  - BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors
JF  - Tumor Biology
VL  - 2017
IS  - October
SP  - 1-11
EP  - 1-11
PB  - Springer Netherlands
SN  - 10104283
KW  - DNA damage response
KW  - BRCA1
KW  - CDK12
KW  - CHK1 inhibitor
KW  - transcription
UR  - https://doi.org/10.1177/1010428317727479
N2  - A broad spectrum of tumors develop resistance to classic chemotherapy, necessitating the discovery of new therapies. One successful strategy exploits the synthetic lethality between poly(ADP-ribose) polymerase 1/2 proteins and DNA damage response genes, including BRCA1, a factor involved in homologous recombination–mediated DNA repair, and CDK12, a transcriptional kinase known to regulate the expression of DDR genes. CHK1 inhibitors have been shown to enhance the anti-cancer effect of DNA-damaging compounds. Since loss of BRCA1 increases replication stress and leads to DNA damage, we tested a hypothesis that CDK12- or BRCA1-depleted cells rely extensively on S-phase-related CHK1 functions for survival. The silencing of BRCA1 or CDK12 sensitized tumor cells to CHK1 inhibitors in vitro and in vivo. BRCA1 downregulation combined with CHK1 inhibition induced excessive amounts of DNA damage, resulting in an inability to complete the S-phase. Therefore, we suggest CHK1 inhibition as a strategy for targeting BRCA1- or CDK12-deficient tumors.
ER  -

PACULOVÁ, Hana, Juraj KRAMARA, Šárka ŠIMEČKOVÁ, Radek FEDR, Karel SOUČEK, Ondřej HYLSE, Kamil PARUCH, Marek SVOBODA, Martin MISTRÍK a Jiří KOHOUTEK. BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors. \textit{Tumor Biology}. Springer Netherlands, 2017, roč.~2017, October, s.~1-11. ISSN~1010-4283. Dostupné z: https://dx.doi.org/10.1177/1010428317727479.

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