An intramolecular G-quadruplex structure with mixed parallel/antiparallel G-strands formed in the human BCL-2 promoter region in solution

被引:350
作者
Dai, JX
Dexheimer, TS
Chen, D
Carver, M
Ambrus, A
Jones, RA
Yang, DZ [1 ]
机构
[1] Univ Arizona, Coll Pharm, Tucson, AZ 85721 USA
[2] Arizona Canc Ctr, Tucson, AZ 85724 USA
[3] Rutgers State Univ, Dept Chem & Chem Biol, Piscataway, NJ 08854 USA
关键词
D O I
10.1021/ja055636a
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
We report the first G-quadruplex structure formed in the promoter region of the human bcl-2. Bcl-2 is a potent oncoprotein that functions as an inhibitor of cell apoptosis and has been found to be aberrantly overexpressed in a wide range of human tumors. A highly GC-rich region upstream of the P1 promoter plays an important role in the regulation of the transcriptional activity of the bcl-2 oncogene. The purine-rich strand of this region contains multiple runs of guanines and can form three distinct intramolecular G-quadruplexes in K+-containing solution. Of these, the G-quadruplex formed within the middle four consecutive guanine runs has been shown to be the most stable G-quadruplex structure, while it is also a mixture of loop isomers. The predominant G-quadruplex structure formed in this region was studied by NMR. Our results demonstrate a novel folding of a unique intramolecular G-quadruplex structure with mixed parallel/antiparallel G-strands. This G-quadruplex structure contains three G-tetrads connected with a single-nucleotide double-chain-reversal side loop and two lateral loops. The first three-nucleotide CGC loop in the bcl-2 promoter sequence forms a lateral loop, as opposed to a double-chain-reversal side loop observed in a similar sequence in the c-MYC promoter, which appears to largely determine the overall folding of the bcl-2 G-quadruplex. Furthermore, both the bcl-2 and c-MYC promoter sequences contain the G3NG3 sequence motif, which forms a stable double-chain-reversal, parallel-stranded structural motif. This predominant bcl-2 G-quadruplex represents an attractive novel target for the design of new anticancer drugs that specifically modulate bcl-2 gene expression. Copyright © 2006 American Chemical Society.
引用
收藏
页码:1096 / 1098
页数:3
相关论文
共 29 条
[1]   EXPRESSION OF BCL-2 PROTEIN AND BCL-2 MESSENGER-RNA IN NORMAL AND NEOPLASTIC LYMPHOID-TISSUES [J].
AKAGI, T ;
KONDO, E ;
YOSHINO, T .
LEUKEMIA & LYMPHOMA, 1994, 13 (1-2) :81-87
[2]   Solution structure of the biologically relevant g-quadruplex element in the human c-MYC promoter. implications for g-quadruplex stabilization [J].
Ambrus, A ;
Chen, D ;
Dai, JX ;
Jones, RA ;
Yang, DZ .
BIOCHEMISTRY, 2005, 44 (06) :2048-2058
[3]  
Baretton GB, 1996, CANCER, V77, P255, DOI 10.1002/(SICI)1097-0142(19960115)77:2<255::AID-CNCR6>3.0.CO
[4]  
2-L
[5]   Novel DNA bis-intercalation by MLN944, a potent clinical bisphenazine anticancer drug [J].
Dai, JX ;
Punchihewa, C ;
Mistry, P ;
Ooi, AT ;
Yang, DZ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (44) :46096-46103
[6]   Evidence for the presence of a guanine quadruplex forming region within a polypurine tract of the hypoxia inducible factor 1α promoter [J].
De Armond, R ;
Wood, S ;
Sun, DY ;
Hurley, LH ;
Ebbinghaus, SW .
BIOCHEMISTRY, 2005, 44 (49) :16341-16350
[7]  
DEXHEIMER TS, 2005, UNPUB J AM CHEM SOC
[8]   Drug recognition and stabilisation of the parallel-stranded DNA quadruplex d(TTAGGGT)4 containing the human telomeric repeat [J].
Gavathiotis, E ;
Heald, RA ;
Stevens, MFG ;
Searle, MS .
JOURNAL OF MOLECULAR BIOLOGY, 2003, 334 (01) :25-36
[9]   The WT1 protein is a negative regulator of the normal bcl-2 allele in t(14;18) lymphomas [J].
Heckman, C ;
Mochon, E ;
Arcinas, M ;
Boxer, LM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (31) :19609-19614
[10]   BCL-2 IS AN INNER MITOCHONDRIAL-MEMBRANE PROTEIN THAT BLOCKS PROGRAMMED CELL-DEATH [J].
HOCKENBERY, D ;
NUNEZ, G ;
MILLIMAN, C ;
SCHREIBER, RD ;
KORSMEYER, SJ .
NATURE, 1990, 348 (6299) :334-336