Damage-induced DNA replication stalling relies on MAPK-activated protein kinase 2 activity
2013 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, no 42, 16856-16861 p.Article in journal (Refereed) Published
DNA damage can obstruct replication forks, resulting in replicative stress. By siRNA screening, we identified kinases involved in the accumulation of phosphohistone 2AX (gamma H2AX) upon UV irradiation-induced replication stress. Surprisingly, the strongest reduction of phosphohistone 2AX followed knockdown of the MAP kinase-activated protein kinase 2 (MK2), a kinase currently implicated in p38 stress signaling and G2 arrest. Depletion or inhibition of MK2 also protected cells from DNA damage-induced cell death, and mice deficient for MK2 displayed decreased apoptosis in the skin upon UV irradiation. Moreover, MK2 activity was required for damage response, accumulation of ssDNA, and decreased survival when cells were treated with the nucleoside analogue gemcitabine or when the checkpoint kinase Chk1 was antagonized. By using DNA fiber assays, we found that MK2 inhibition or knockdown rescued DNA replication impaired by gemcitabine or by Chk1 inhibition. This rescue strictly depended on transiesion DNA polymerases. In conclusion, instead of being an unavoidable consequence of DNA damage, alterations of replication speed and origin firing depend on MK2-mediated signaling.
Place, publisher, year, edition, pages
2013. Vol. 110, no 42, 16856-16861 p.
Engineering and Technology Natural Sciences
IdentifiersURN: urn:nbn:se:su:diva-96094DOI: 10.1073/pnas.1304355110ISI: 000325634200042OAI: oai:DiVA.org:su-96094DiVA: diva2:664200
Wilhelm Sander Stiftung; Deutsche Jose Carreras Stiftung; German Cancer Aid/Dr. Mildred Scheel Stiftung; European Union p53 BM0703; German Research Foundation (Deutsche Forschungsgemeinschaft); Studienstiftung des Deutschen Volkes; Gottingen Graduate School of Neurosciences and Molecular Biosciences 2013-11-142013-11-112014-01-08Bibliographically approved