Abstract

A key control point in gene expression is the initiation of protein translation, with a
universal stress response being constituted by inhibitory phosphorylation of the
eukaryotic initiation factor 2α (eIF2α). In humans, four kinases sense diverse
physiological stresses to regulate eIF2α to control cell differentiation, adaptation, and
survival. Here we develop a computational molecular model of eIF2α and one of its
kinases, the protein kinase R, to simulate the dynamics of their interaction. Predictions
generated by coarse-grained dynamics simulations suggest a novel mode of action.
Experimentation substantiates these predictions, identifying a previously unrecognized
interface in the protein complex, which is constituted by dynamic residues in both eIF2α
and its kinases that are crucial to regulate protein translation. These findings call for a
reinterpretation of the current mechanism of action of the eIF2α kinases and demonstrate
the value of conducting computational analysis to evaluate protein function.

J Mol Cell Biol mju044 first published online November 17, 2014 doi:10.1093/jmcb/mju044

Keywords: molecular dynamics, eukaryotic initiation factor 2α (eIF2α), eIF2α kinases,
protein kinase R (PKR), protein translation, kinase activity

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Abstract

The serine/threonine kinase CHK2 is a key component of the DNA damage response. In
human cells, following genotoxic stress, CHK2 is activated and phosphorylates more than 20
proteins to induce the appropriate cellular response, which, depending on the extent of damage,
the cell type, and other factors, could be cell cycle checkpoint activation, induction of apoptosis
or senescence, DNA repair, or tolerance of the damage. Recently, CHK2 has also been found to
have cellular functions independent of the presence of nuclear DNA lesions. In particular, CHK2
participates in several molecular processes involved in DNA structure modification and cell
cycle progression. In this review, we discuss the activity of CHK2 in response to DNA damage
and in the maintenance of the biological functions in unstressed cells. These activities are also
considered in relation to a possible role of CHK2 in tumorigenesis and, as a consequence, as a
target of cancer therapy.

J Mol Cell Biol mju045 first published online November 17, 2014 doi:10.1093/jmcb/mju045

Keywords: DNA damage, checkpoints, apoptosis, genomic stability 

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