BET inhibition induces HEXIM1- and RAD51-dependent conflicts between transcription and replication

Akhil Bowry; Ann Liza Piberger; Patricia Rojas; Marco Saponaro; Eva Petermann

doi:10.1016/j.celrep.2018.10.079

BET inhibition induces HEXIM1- and RAD51-dependent conflicts between transcription and replication

Akhil Bowry
, Ann Liza Piberger
, Patricia Rojas
, Marco Saponaro
, Eva Petermann

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

16 Citations (Scopus)

375 Downloads (Pure)

Abstract

BET bromodomain proteins are required for oncogenic transcription activities, and BET inhibitors have been rapidly advanced into clinical trials. Understanding the effects of BET inhibition on processes such as DNA replication will be important for future clinical applications. Here we show that BET inhibition, and specifically inhibition of BRD4, causes replication stress through a rapid overall increase in RNA synthesis. We provide evidence that BET inhibition acts by releasing P-TEFb from its inhibitor HEXIM1, promoting interference between transcription and replication. Unusually, these transcription-replication conflicts do not activate the ATM/ATR-dependent DNA damage response, but recruit the homologous recombination factor RAD51. Both HEXIM1 and RAD51 promote BET inhibitor-induced fork slowing, but also prevent a DNA damage response. Our data suggest that BET inhibitors slow replication through concerted action of transcription and recombination machineries, and shed light on the importance of replication stress in the action of this class of experimental cancer drugs.

Original language	English
Pages (from-to)	2061–2069.e4
Number of pages	13
Journal	Cell Reports
Volume	25
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2018.10.079
Publication status	Published - 20 Nov 2018

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

BRD4
DNA damage
I-BET151
JQ1
P-TEFb
cancer
homologous recombination
replication fork
replication stress

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10.1016/j.celrep.2018.10.079Licence: Creative Commons: Attribution (CC BY)

BowryA2018BETinhibitionFinal published version, 2.41 MBLicence: Creative Commons: Attribution (CC BY)

16 Citations
2 Article
1 Poster

BET inhibition induces transcription-replication conflicts that depend on HEXIM1 and RAD51
Bowry, A., Piberger, A. L. & Petermann, E., Oct 2018.
Research output: Contribution to conference (unpublished) › Poster
Increased global transcription activity as a mechanism of replication stress in cancer
Kotsantis, P., Marques Silva, L., Irmscher, S., Jones, R., Folkes, L., Gromak, N. & Petermann, E., Dec 2016, In: Nature Communications. 7, 1, 13 p., 13087.
Research output: Contribution to journal › Article › peer-review

Open Access
File
114 Citations (Scopus)

304 Downloads (Pure)
BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia
Da Costa, D., Agathanggelou, A., Perry, T., Weston, V., Petermann, E., Zlatanou, A., Oldreive, C., Wei, W., Stewart, G., Longman, J., Smith, E., Kearns, P., Knapp, S. & Stankovic, T., Jul 2013, In: Blood Cancer Journal. 3, 7, e126.
Research output: Contribution to journal › Article › peer-review

Open Access
File
62 Citations (Scopus)

273 Downloads (Pure)

Interference Between Replication and Transcription as a Mechanism of Oncogene-Induced DNA Damage
Petermann, E. (Principal Investigator)
WORLDWIDE CANCER RESEARCH
1/11/13 → 31/10/16
Project: Research

Invited Speaker: International Workshop on Chromosomal Instability.
Petermann, E. (Invited speaker)
Jun 2024
Activity: Academic and Industrial events › Guest lecture or Invited talk
Invited Speaker: The Mark Foundation Workshop on Chromosomal Instability.
Petermann, E. (Invited speaker)
27 Jun 2023
Activity: Academic and Industrial events › Guest lecture or Invited talk
Invited Speaker: UK DNA Replication meeting 2022
Petermann, E. (Invited speaker)
7 Sept 2022
Activity: Academic and Industrial events › Guest lecture or Invited talk
Proffered Paper Speaker: Japan-UK Regulation through Chromatin Conference 2022
Petermann, E. (Speaker)
23 Aug 2022
Activity: Academic and Industrial events › Guest lecture or Invited talk
Invited Speaker: Fourth international course on genome instability and human disease, Institut Curie
Petermann, E. (Invited speaker)
14 Feb 2022
Activity: Academic and Industrial events › Guest lecture or Invited talk
Invited Speaker: EMBO | EMBL Symposium Friend or Foe: Transcription and RNA Meet DNA Replication and Repair
Petermann, E. (Invited speaker)
12 Mar 2021
Activity: Academic and Industrial events › Guest lecture or Invited talk

Cite this

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title = "BET inhibition induces HEXIM1- and RAD51-dependent conflicts between transcription and replication",

abstract = "BET bromodomain proteins are required for oncogenic transcription activities, and BET inhibitors have been rapidly advanced into clinical trials. Understanding the effects of BET inhibition on processes such as DNA replication will be important for future clinical applications. Here we show that BET inhibition, and specifically inhibition of BRD4, causes replication stress through a rapid overall increase in RNA synthesis. We provide evidence that BET inhibition acts by releasing P-TEFb from its inhibitor HEXIM1, promoting interference between transcription and replication. Unusually, these transcription-replication conflicts do not activate the ATM/ATR-dependent DNA damage response, but recruit the homologous recombination factor RAD51. Both HEXIM1 and RAD51 promote BET inhibitor-induced fork slowing, but also prevent a DNA damage response. Our data suggest that BET inhibitors slow replication through concerted action of transcription and recombination machineries, and shed light on the importance of replication stress in the action of this class of experimental cancer drugs.",

keywords = "BRD4, DNA damage, I-BET151, JQ1, P-TEFb, cancer, homologous recombination, replication fork, replication stress",

author = "Akhil Bowry and Piberger, \{Ann Liza\} and Patricia Rojas and Marco Saponaro and Eva Petermann",

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doi = "10.1016/j.celrep.2018.10.079",

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AU - Bowry, Akhil

AU - Piberger, Ann Liza

AU - Rojas, Patricia

AU - Saponaro, Marco

AU - Petermann, Eva

PY - 2018/11/20

Y1 - 2018/11/20

N2 - BET bromodomain proteins are required for oncogenic transcription activities, and BET inhibitors have been rapidly advanced into clinical trials. Understanding the effects of BET inhibition on processes such as DNA replication will be important for future clinical applications. Here we show that BET inhibition, and specifically inhibition of BRD4, causes replication stress through a rapid overall increase in RNA synthesis. We provide evidence that BET inhibition acts by releasing P-TEFb from its inhibitor HEXIM1, promoting interference between transcription and replication. Unusually, these transcription-replication conflicts do not activate the ATM/ATR-dependent DNA damage response, but recruit the homologous recombination factor RAD51. Both HEXIM1 and RAD51 promote BET inhibitor-induced fork slowing, but also prevent a DNA damage response. Our data suggest that BET inhibitors slow replication through concerted action of transcription and recombination machineries, and shed light on the importance of replication stress in the action of this class of experimental cancer drugs.

AB - BET bromodomain proteins are required for oncogenic transcription activities, and BET inhibitors have been rapidly advanced into clinical trials. Understanding the effects of BET inhibition on processes such as DNA replication will be important for future clinical applications. Here we show that BET inhibition, and specifically inhibition of BRD4, causes replication stress through a rapid overall increase in RNA synthesis. We provide evidence that BET inhibition acts by releasing P-TEFb from its inhibitor HEXIM1, promoting interference between transcription and replication. Unusually, these transcription-replication conflicts do not activate the ATM/ATR-dependent DNA damage response, but recruit the homologous recombination factor RAD51. Both HEXIM1 and RAD51 promote BET inhibitor-induced fork slowing, but also prevent a DNA damage response. Our data suggest that BET inhibitors slow replication through concerted action of transcription and recombination machineries, and shed light on the importance of replication stress in the action of this class of experimental cancer drugs.

KW - BRD4

KW - DNA damage

KW - I-BET151

KW - JQ1

KW - P-TEFb

KW - cancer

KW - homologous recombination

KW - replication fork

KW - replication stress

U2 - 10.1016/j.celrep.2018.10.079

DO - 10.1016/j.celrep.2018.10.079

M3 - Article

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SN - 2211-1247

VL - 25

SP - 2061–2069.e4

JO - Cell Reports

JF - Cell Reports

IS - 8

ER -

BET inhibition induces HEXIM1- and RAD51-dependent conflicts between transcription and replication

Abstract

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Keywords

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