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.

Basic information

Original name

BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors

Authors

PACULOVÁ, Hana (203 Czech Republic), Juraj KRAMARA (703 Slovakia), Šárka ŠIMEČKOVÁ (203 Czech Republic, belonging to the institution), Radek FEDR (203 Czech Republic), Karel SOUČEK (203 Czech Republic, belonging to the institution), Ondřej HYLSE (203 Czech Republic, belonging to the institution), Kamil PARUCH (203 Czech Republic, guarantor, belonging to the institution), Marek SVOBODA (203 Czech Republic), Martin MISTRÍK (203 Czech Republic) and Jiří KOHOUTEK (203 Czech Republic)

Edition

Tumor Biology, Springer Netherlands, 2017, 1010-4283

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10401 Organic chemistry

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 3.650 in 2016

RIV identification code

RIV/00216224:14310/17:00097945

Organization unit

Faculty of Science

DOI

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

Keywords in English

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

Abstract

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.

Links

LM2015063, research and development project

Name: Národní infrastruktura chemické biologie (Acronym: CZ-OPENSCREEN)

Investor: Ministry of Education, Youth and Sports of the CR

Citovat

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

Detailed Information on Publication Record