Universität zu Köln

Reinhardt, H. Christian, Hasskamp, Pia, Schmedding, Ingolf, Morandell, Sandra, van Vugt, Marcel A. T. M., Wang, XiaoZhe, Linding, Rune ORCID: 0000-0003-0420-4839, Ong, Shao-En, Weaver, David, Carr, Steven A. and Yaffe, Michael B. (2010). DNA Damage Activates a Spatially Distinct Late Cytoplasmic Cell-Cycle Checkpoint Network Controlled by MK2-Mediated RNA Stabilization. Mol. Cell, 40 (1). S. 34 - 50. CAMBRIDGE: CELL PRESS. ISSN 1097-4164

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Abstract

Following genotoxic stress, cells activate a complex kinase-based signaling network to arrest the cell cycle and initiate DNA repair. p53-defective tumor cells rewire their checkpoint response and become dependent on the p38/MK2 pathway for survival after DNA damage, despite a functional ATR-Chk1 pathway. We used functional genetics to dissect the contributions of Chk1 and MK2 to checkpoint control. We show that nuclear Chk1 activity is essential to establish a G(2)/M checkpoint, while cytoplasmic MK2 activity is critical for prolonged checkpoint maintenance through a process of post-transcriptional mRNA stabilization. Following DNA damage, the p38/MK2 complex relocalizes from nucleus to cytoplasm where MK2 phosphorylates hnRNPA0, to stabilize Gadd45 alpha mRNA, while p38 phosphorylates and releases the translational inhibitor TIAR. In addition, MK2 phosphorylates PARN, blocking Gadd45 alpha mRNA degradation. Gadd45a functions within a positive feedback loop, sustaining the MK2-dependent cytoplasmic sequestration of Cdc25B/C to block mitotic entry in the presence of unrepaired DNA damage. Our findings demonstrate a critical role for the MK2 pathway in the posttranscriptional regulation of gene expression as part of the DNA damage response in cancer cells.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Reinhardt, H. Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Hasskamp, Pia UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmedding, Ingolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Morandell, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED van Vugt, Marcel A. T. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, XiaoZhe UNSPECIFIED UNSPECIFIED UNSPECIFIED Linding, Rune UNSPECIFIED orcid.org/0000-0003-0420-4839 UNSPECIFIED Ong, Shao-En UNSPECIFIED UNSPECIFIED UNSPECIFIED Weaver, David UNSPECIFIED UNSPECIFIED UNSPECIFIED Carr, Steven A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Yaffe, Michael B. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-494400
DOI:	10.1016/j.molcel.2010.09.018
Journal or Publication Title:	Mol. Cell
Volume:	40
Number:	1
Page Range:	S. 34 - 50
Date:	2010
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1097-4164
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ONCOGENE-INDUCED SENESCENCE; AU-RICH ELEMENTS; CANCER-CELLS; MEDIATE ACTIVATION; KINASE ACTIVATION; MAPKAP KINASE-2; NUCLEAR EXPORT; CHK1; P38; PHOSPHORYLATION Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/49440