The KRAS Promoter Responds to Myc-associated Zinc Finger and Poly(ADP-ribose) Polymerase 1 Proteins, Which Recognize a Critical Quadruplex-forming GA-element

被引:123
作者
Cogoi, Susanna [1 ]
Paramasivam, Manikandan [1 ]
Membrino, Alexandro [1 ]
Yokoyama, Kazunari K. [2 ]
Xodo, Luigi E. [1 ]
机构
[1] Univ Udine, Sch Med, Dept Biomed Sci & Technol, I-33100 Udine, Italy
[2] Kaohsiung Med Univ, Ctr Excellence Environm Med, Kaohsiung 80708, Taiwan
关键词
NUCLEASE HYPERSENSITIVE ELEMENT; C-MYC; DNA-STRUCTURE; GENE-EXPRESSION; P2; PROMOTER; G4; DNA; BINDING; MAZ; TRANSCRIPTION; PARP-1;
D O I
10.1074/jbc.M110.101923
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The murine KRAS promoter contains a G-rich nuclease hypersensitive element (GA-element) upstream of the transcription start site that is essential for transcription. Pulldown and chromatin immunoprecipitation assays demonstrate that this GA-element is bound by the Myc-associated zinc finger (MAZ) and poly(ADP-ribose) polymerase 1 (PARP-1) proteins. These proteins are crucial for transcription, because when they are knocked down by short hairpin RNA, transcription is down-regulated. This is also the case when the poly(ADP-ribosyl) ation activity of PARP-1 is inhibited by 3,4-dihydro-5-[ 4-(1-piperidinyl) butoxyl]-1(2H) isoquinolinone. We found that MAZ specifically binds to the duplex and quadruplex conformations of the GA-element, whereas PARP-1 shows specificity only for the G-quadruplex. On the basis of fluorescence resonance energy transfer melting and polymerase stop assays we saw that MAZ stabilizes the KRAS quadruplex. When the capacity of folding in the GA-element is abrogated by specific G -> T or G -> A point mutations, KRAS transcription is down-regulated. Conversely, guanidine-modified phthalocyanines, which specifically interact with and stabilize the KRAS G-quadruplex, push the promoter activity up to more than double. Collectively, our data support a transcription mechanism for murine KRAS that involves MAZ, PARP-1 and duplex-quadruplex conformational changes in the promoter GA-element.
引用
收藏
页码:22003 / 22016
页数:14
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