Methyltransferase Set7/9 regulates p53 activity by interacting with Sirtuin 1 (SIRT1).
Numerous studies indicate that Sirtuin 1 (SIRT1), a mammalian nicotinamide adenine dinucleotide (NAD(+))-dependent histone deacetylase (HDAC), plays a crucial role in p53-mediated stress responses by deacetylating p53. Nevertheless, the acetylation levels of p53 are dramatically increased upon DNA damage, and it is not well understood how the SIRT1-p53 interaction is regulated during the stress responses. Here, we identified Set7/9 as a unique regulator of SIRT1. SIRT1 interacts with Set7/9 both in vitro and in vivo. In response to DNA damage in human cells, the interaction between Set7/9 and SIRT1 is significantly enhanced and coincident with an increase in p53 acetylation levels. Importantly, the interaction of SIRT1 and p53 is strongly suppressed in the presence of Set7/9. Consequently, SIRT1-mediated deacetylation of p53 is abrogated by Set7/9, and p53-mediated transactivation is increased during the DNA damage response. Of note, whereas SIRT1 can be methylated at multiple sites within its N terminus by Set7/9, a methylation-defective mutant of SIRT1 still retains its ability to inhibit p53 activity. Taken together, our results reveal that Set7/9 is a critical regulator of the SIRT1-p53 interaction and suggest that Set7/9 can modulate p53 function indirectly in addition to acting through a methylation-dependent mechanism.
Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
Xiangyu
X
Liu
Donglai
D
Wang
Ying
Y
Zhao
Bo
B
Tu
Zhixing
Z
Zheng
Lina
L
Wang
Haiying
H
Wang
Wei
W
Gu
Robert G
RG
Roeder
Wei-Guo
WG
Zhu
D000107:Acetylation; D002460:Cell Line; D006801:Humans; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism*; D011485:Protein Binding; D056564:Sirtuin 1 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D008780:Methyltransferases; D056564:Sirtuin 1
Science. 2004 Mar 26;303(5666):2011-5
14976264
Nature. 2008 Jan 31;451(7178):587-90
18235502
J Biol Chem. 2005 Oct 28;280(43):36244-53
16141209
Nat Cell Biol. 2007 Nov;9(11):1253-62
17934453
Nat Cell Biol. 2010 Jul;12(7):665-75
20543840
Cell Cycle. 2008 Oct;7(19):3091-7
18838864
Mol Cell Biol. 2007 Oct;27(19):6756-69
17646389
Cancer Res. 2005 Nov 15;65(22):10457-63
16288037
Mol Cell. 2008 Feb 15;29(3):392-400
18280244
Biochem Biophys Res Commun. 2009 Apr 10;381(3):372-7
19236849
Leukemia. 2005 Oct;19(10):1751-9
16121216
Nature. 2008 Jan 31;451(7178):583-6
18235501
Diabetes. 2009 Jan;58(1):185-93
18984737
Mol Cell. 2004 Apr 23;14(2):175-82
15099517
Epigenetics. 2009 Aug 16;4(6):383-7
19684477
Mol Cell. 2007 Oct 26;28(2):277-90
17964266
Annu Rev Biochem. 2004;73:417-35
15189148
Genes Dev. 2002 Feb 15;16(4):479-89
11850410
Cell. 2005 Nov 4;123(3):437-48
16269335
Cell. 2001 Oct 19;107(2):149-59
11672523
Oncogene. 2010 Apr 22;29(16):2357-67
20140018
Cell. 2001 Oct 19;107(2):137-48
11672522
Nature. 2000 Feb 17;403(6771):795-800
10693811
Nature. 2004 Nov 18;432(7015):353-60
15525938
Nat Genet. 2009 Jan;41(1):125-9
19098913
Cancer Res. 2007 Jul 15;67(14):6612-8
17638871
Proc Natl Acad Sci U S A. 2009 Mar 31;106(13):5076-81
19282482
Mol Cell. 2001 Dec;8(6):1207-17
11779497
J Biol Chem. 2010 Apr 23;285(17):13223-32
20167603
Cell. 1997 Aug 22;90(4):595-606
9288740
Cell. 2004 Feb 20;116(4):551-63
14980222
PLoS One. 2009 Aug 14;4(8):e6611
19680552