HDAC1 and HDAC2 integrate checkpoint kinase phosphorylation and cell fate through the phosphatase-2A subunit PR130

Nature Communications
Anja GöderO H Krämer

Abstract

Checkpoint kinases sense replicative stress to prevent DNA damage. Here we show that the histone deacetylases HDAC1/HDAC2 sustain the phosphorylation of the checkpoint kinases ATM, CHK1 and CHK2, activity of the cell cycle gatekeeper kinases WEE1 and CDK1, and induction of the tumour suppressor p53 in response to stalled DNA replication. Consequently, HDAC inhibition upon replicative stress promotes mitotic catastrophe. Mechanistically, HDAC1 and HDAC2 suppress the expression of PPP2R3A/PR130, a regulatory subunit of the trimeric serine/threonine phosphatase 2 (PP2A). Genetic elimination of PR130 reveals that PR130 promotes dephosphorylation of ATM by PP2A. Moreover, the ablation of PR130 slows G1/S phase transition and increases the levels of phosphorylated CHK1, replication protein A foci and DNA damage upon replicative stress. Accordingly, stressed PR130 null cells are very susceptible to HDAC inhibition, which abrogates the S phase checkpoint, induces apoptosis and reduces the homologous recombination protein RAD51. Thus, PR130 controls cell fate decisions upon replicative stress.

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Citations

Jan 15, 2020·Journal of Cancer Research and Clinical Oncology·Nicole KiwelerOliver H Krämer
Jun 17, 2020·Experimental and Therapeutic Medicine·Huiwu LiLing Liu
Jul 9, 2020·International Journal of Molecular Sciences·Annabelle FriedrichGerhard Fritz
Sep 29, 2020·Frontiers in Cell and Developmental Biology·Dhanach DhirachaikulpanichLuminita Paraoan
Jan 16, 2020·International Journal of Molecular Sciences·Adrián Campos, Andrés Clemente-Blanco
Mar 16, 2019·Epigenetics & Chromatin·Kathrin S HeinzM Cristina Cardoso
Oct 30, 2020·Frontiers in Cell and Developmental Biology·Guo LiWei-Guo Zhu
Mar 20, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Ting-Yu ChangSung-Bau Lee
May 31, 2021·Trends in Cancer·Akhil BowryEva Petermann

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Methods Mentioned

BETA
Flow cytometry
transfection
PCR
immunoprecipitation
Co-immunoprecipitations
acetylation
histone acetylation
Biosample
X-ray
Co-IP

Software Mentioned

Flowing
FACSDiva
ImageJ
Image Studio Lite
LSM Image Browser

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