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Published on: June 26, 2020
Damage-induced DNA replication stalling relies on MAPK-activated protein kinase 2 activity
Frederik Köpper1, Cathrin Bierwirth, Margarete Schön
1Institute of Molecular Oncology and Göttingen Centre of Molecular Biosciences, Faculty of Medicine, University of Göttingen, 37077 Göttingen, Germany.
Summary
MAP kinase-activated protein kinase 2 (MK2) plays a key role in DNA damage response. MK2 inhibition protects cells from DNA damage and rescues replication forks, revealing its importance in cell survival signaling.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- DNA damage can stall replication forks, leading to replication stress.
- Kinases are crucial in managing cellular responses to DNA damage and replication stress.
Purpose of the Study:
- To identify kinases involved in the accumulation of phosphohistone 2AX (γH2AX) during UV-induced replication stress.
- To investigate the role of MAP kinase-activated protein kinase 2 (MK2) in DNA damage response and replication fork stability.
Main Methods:
- siRNA screening to identify key kinases.
- Analysis of phosphohistone 2AX (γH2AX) accumulation.
- Cell viability assays and apoptosis measurements in MK2-deficient mice.
- DNA fiber assays to assess replication fork dynamics.
- Treatment with gemcitabine and Chk1 antagonism.
Main Results:
- Knockdown of MK2 significantly reduced γH2AX accumulation after UV irradiation.
- MK2 depletion or inhibition conferred resistance to DNA damage-induced cell death.
- MK2 deficiency reduced UV-induced apoptosis in mouse skin.
- MK2 activity was essential for DNA damage response, ssDNA accumulation, and reduced cell survival upon gemcitabine treatment or Chk1 inhibition.
- MK2 inhibition or knockdown rescued impaired DNA replication, dependent on translesion DNA polymerases.
Conclusions:
- MK2 signaling is a critical regulator of replication fork dynamics and origin firing following DNA damage.
- MK2 inhibition offers a potential therapeutic strategy to protect against DNA damage and enhance cancer treatment efficacy.
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