Damage-induced DNA replication stalling relies on MAPK-activated protein kinase 2 activity

被引:62
作者
Koepper, Frederik [1 ,2 ]
Bierwirth, Cathrin [1 ,2 ]
Schoen, Margarete [3 ]
Kunze, Meike [1 ,2 ]
Elvers, Ingegerd [4 ]
Kranz, Dominique [5 ]
Saini, Priyanka [1 ,2 ]
Menon, Manoj B. [6 ]
Walter, David [7 ]
Sorensen, Claus Storgaard [7 ]
Gaestel, Matthias [6 ]
Helleday, Thomas [8 ]
Schoen, Michael P. [3 ]
Dobbelstein, Matthias [1 ,2 ]
机构
[1] Univ Gottingen, Inst Mol Oncol, D-37077 Gottingen, Germany
[2] Univ Gottingen, Fac Med, Gottingen Ctr Mol Biosci, D-37077 Gottingen, Germany
[3] Univ Gottingen, Fac Med, Dept Dermatol Venereol & Allergol, D-37099 Gottingen, Germany
[4] Stockholm Univ, Dept Genet Microbiol & Toxicol, S-10691 Stockholm, Sweden
[5] Univ Southern Denmark, Inst Med Biol, DK-5230 Odense, Denmark
[6] Hannover Med Sch, Inst Biochem, D-30623 Hannover, Germany
[7] Univ Copenhagen, Biotech Res & Innovat Ctr, DK-2200 Copenhagen, Denmark
[8] Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab, SE-17177 Solna, Sweden
关键词
CYCLE CHECKPOINT KINASE; VERTEBRATE S-PHASE; HUMAN-CELLS; H2AX PHOSPHORYLATION; RNA STABILIZATION; FORK PROGRESSION; POLYMERASE-ETA; CHK1; STRESS; ORIGINS;
D O I
10.1073/pnas.1304355110
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:16856 / 16861
页数:6
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