title: Regulation of HuR by DNA Damage Response Kinases.
abstract: As many DNA-damaging conditions repress transcription, posttranscriptional processes critically influence gene expression during the genotoxic stress response. The RNA-binding protein HuR robustly influences gene expression following DNA damage. HuR function is controlled in two principal ways: (1) by mobilizing HuR from the nucleus to the cytoplasm, where it modulates the stability and translation of target mRNAs and (2) by altering its association with target mRNAs. Here, we review evidence that two main effectors of ataxia-telangiectasia-mutated/ATM- and Rad3-related (ATM/ATR), the checkpoint kinases Chk1 and Chk2, jointly influence HuR function. Chk1 affects HuR localization by phosphorylating (hence inactivating) Cdk1, a kinase that phosphorylates HuR and thereby blocks HuR's cytoplasmic export. Chk2 modulates HuR binding to target mRNAs by phosphorylating HuR's RNA-recognition motifs (RRM1 and RRM2). We discuss how HuR phosphorylation by kinases including Chk1/Cdk1 and Chk2 impacts upon gene expression patterns, cell proliferation, and survival following genotoxic injury.
authors.affiliation: Laboratory of Cellular and Molecular Biology, NIA-IRP, NIH, Baltimore, MD 21224, USA.
authors.forename: Hyeon Ho
authors.initials: HH
authors.lastname: Kim
authors.forename: Kotb
authors.initials: K
authors.lastname: Abdelmohsen
authors.forename: Myriam
authors.initials: M
authors.lastname: Gorospe
references.citation: Mol Cell Biol. 2009 Aug;29(16):4341-51
references.pmid: 19528229
references.citation: Science. 2001 Nov 30;294(5548):1895-901
references.pmid: 11729309
references.citation: Mol Biol Cell. 2001 Mar;12(3):551-63
references.pmid: 11251070
references.citation: Genes Dev. 2003 Dec 15;17(24):3062-74
references.pmid: 14681206
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2918-23
references.pmid: 14981248
references.citation: Genes Dev. 2009 Aug 1;23(15):1743-8
references.pmid: 19574298
references.citation: Science. 1999 Dec 24;286(5449):2528-31
references.pmid: 10617473
references.citation: Mol Cell Biol. 2003 Oct;23(20):7177-88
references.pmid: 14517288
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20297-302
references.pmid: 19088191
references.citation: Curr Opin Cell Biol. 2009 Apr;21(2):245-55
references.pmid: 19230643
references.citation: Mol Cell. 2006 Apr 7;22(1):117-28
references.pmid: 16600875
references.citation: Cancer Res. 2001 Mar 1;61(5):2154-61
references.pmid: 11280780
references.citation: EMBO J. 2004 Aug 4;23(15):3092-102
references.pmid: 15257295
references.citation: J Biol Chem. 2004 Nov 12;279(46):48376-88
references.pmid: 15342649
references.citation: Int J Radiat Biol. 2009 Aug;85(8):643-55
references.pmid: 19579069
references.citation: Nat Rev Mol Cell Biol. 2000 Dec;1(3):179-86
references.pmid: 11252893
references.citation: Genes Dev. 2008 Jul 1;22(13):1804-15
references.pmid: 18593881
references.citation: Mol Cell Biol. 2008 Apr;28(8):2608-25
references.pmid: 18285462
references.citation: Cell Cycle. 2008 Oct;7(20):3124-6
references.pmid: 18927508
references.citation: Science. 2005 Sep 2;309(5740):1514-8
references.pmid: 16141059
references.citation: Mol Cell Biol. 2003 Jul;23(14):4991-5004
references.pmid: 12832484
references.citation: Curr Opin Genet Dev. 2000 Apr;10(2):193-8
references.pmid: 10753781
references.citation: Mol Cell Biol. 2008 Jul;28(14):4562-75
references.pmid: 18490444
references.citation: J Biol Chem. 2003 Nov 21;278(47):47119-28
references.pmid: 12944397
references.citation: Biol Chem. 2008 Mar;389(3):243-55
references.pmid: 18177264
references.citation: Trends Mol Med. 2008 Jul;14(7):305-13
references.pmid: 18539531
references.citation: EMBO J. 2000 May 15;19(10):2340-50
references.pmid: 10811625
references.citation: Cell Mol Life Sci. 2001 Feb;58(2):266-77
references.pmid: 11289308
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2987-92
references.pmid: 14981256
references.citation: Mol Cell. 2007 Feb 23;25(4):543-57
references.pmid: 17317627
references.citation: Genes Dev. 2002 Dec 1;16(23):3087-99
references.pmid: 12464637
references.citation: Mol Cell. 2009 Mar 13;33(5):547-58
references.pmid: 19285939
references.citation: Cell Cycle. 2003 Sep-Oct;2(5):412-4
references.pmid: 12963828
references.citation: J Cell Biol. 2008 Jan 14;180(1):113-27
references.pmid: 18180367
references.citation: Nat Rev Mol Cell Biol. 2001 Dec;2(12):877-86
references.pmid: 11733767
references.citation: Nucleic Acids Res. 2004 Sep 08;32(16):4786-803
references.pmid: 15356296
references.citation: Cell Cycle. 2008 Nov 1;7(21):3371-7
references.pmid: 18948743
references.citation: J Biol Chem. 2003 Sep 26;278(39):37637-47
references.pmid: 12826679
references.citation: J Biol Chem. 1997 May 16;272(20):13229-35
references.pmid: 9148940
references.citation: Curr Opin Genet Dev. 2004 Feb;14(1):11-6
references.pmid: 15108799
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8354-9
references.pmid: 12821781
references.citation: Cell Cycle. 2007 Jun 1;6(11):1288-92
references.pmid: 17534146
references.citation: Nature. 2000 Nov 23;408(6811):433-9
references.pmid: 11100718
references.citation: J Cell Mol Med. 2003 Oct-Dec;7(4):341-50
references.pmid: 14754503
references.citation: Genes Dev. 1999 Jan 15;13(2):152-7
references.pmid: 9925639
references.citation: J Biol Chem. 1998 Mar 13;273(11):6417-23
references.pmid: 9497373
references.citation: Cell Signal. 2008 Dec;20(12):2165-73
references.pmid: 18585896
references.citation: Curr Biol. 2006 Jan 24;16(2):150-9
references.pmid: 16360315
references.citation: Mol Cell Biol. 2001 Jul;21(13):4129-39
references.pmid: 11390642
references.citation: EMBO J. 1998 Jan 2;17(1):159-69
references.pmid: 9427750
references.citation: J Biol Chem. 2009 Dec 4;284(49):34223-30
references.pmid: 19837665
references.citation: Oncogene. 2003 Oct 16;22(46):7146-54
references.pmid: 14562043
references.citation: Nat Rev Genet. 2007 Jul;8(7):533-43
references.pmid: 17572691
references.citation: EMBO J. 2009 May 6;28(9):1271-82
references.pmid: 19322201
references.citation: Cell Cycle. 2010 Apr 1;9(7):1354-9
references.pmid: 20305372
references.citation: EMBO J. 2005 May 18;24(10):1852-62
references.pmid: 15861128
references.citation: Cell. 2009 Jan 23;136(2):215-33
references.pmid: 19167326
references.citation: Adv Cancer Res. 2001;83:209-54
references.pmid: 11665719
references.citation: Mol Biol Cell. 2007 Jun;18(6):2137-48
references.pmid: 17392515
references.citation: J Biol Chem. 2001 Jan 26;276(4):2971-4
references.pmid: 11053450
references.citation: Mutagenesis. 2006 Jan;21(1):3-9
references.pmid: 16314342
references.citation: Cell Mol Life Sci. 2008 Oct;65(20):3168-81
references.pmid: 18581050
references.citation: Biochim Biophys Acta. 2007 Aug;1773(8):1358-75
references.pmid: 17481747
references.citation: Nucleic Acids Res. 2002 May 15;30(10):2251-60
references.pmid: 12000845
references.citation: Proc Natl Acad Sci U S A. 1999 Jan 5;96(1):5-7
references.pmid: 9874760
references.citation: Mol Cell Biol. 2000 Feb;20(3):760-9
references.pmid: 10629032
references.citation: Cell. 2002 Feb 22;108(4):439-51
references.pmid: 11909516
references.citation: Nat Rev Mol Cell Biol. 2002 Jan;3(1):21-9
references.pmid: 11823795
references.citation: Nucleic Acids Res. 2010 May;38(9):3005-18
references.pmid: 20110258
references.citation: Wiley Interdiscip Rev RNA. 2010 Sep-Oct;1(2):214-29
references.pmid: 21935886
references.citation: RNA. 2004 Apr;10(4):590-9
references.pmid: 15037768
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15293-8
references.pmid: 9860962
references.citation: EMBO Rep. 2003 Jul;4(7):671-7
references.pmid: 12835754
references.citation: Am J Hum Genet. 2002 Aug;71(2):432-8
references.pmid: 12094328
references.citation: Int J Biol Sci. 2009;5(1):44-51
references.pmid: 19159010
references.citation: Mol Cell Biol. 2010 Mar;30(6):1397-410
references.pmid: 20086103
references.citation: Mol Cell. 2005 Sep 16;19(6):777-89
references.pmid: 16168373