Unknown

Dataset Information

0

NM23-H2 may play an indirect role in transcriptional activation of c-myc gene expression but does not cleave the nuclease hypersensitive element III(1).


ABSTRACT: The formation of G-quadruplex structures within the nuclease hypersensitive element (NHE) III(1) region of the c-myc promoter and the ability of these structures to repress c-myc transcription have been well established. However, just how these extremely stable DNA secondary structures are transformed to activate c-myc transcription is still unknown. NM23-H2/nucleoside diphosphate kinase B has been recognized as an activator of c-myc transcription via interactions with the NHE III(1) region of the c-myc gene promoter. Through the use of RNA interference, we confirmed the transcriptional regulatory role of NM23-H2. In addition, we find that further purification of NM23-H2 results in loss of the previously identified DNA strand cleavage activity, but retention of its DNA binding activity. NM23-H2 binds to both single-stranded guanine- and cytosine-rich strands of the c-myc NHE III(1) and, to a lesser extent, to a random single-stranded DNA template. However, it does not bind to or cleave the NHE III(1) in duplex form. Significantly, potassium ions and compounds that stabilize the G-quadruplex and i-motif structures have an inhibitory effect on NM23-H2 DNA-binding activity. Mutation of Arg(88) to Ala(88) (R88A) reduced both DNA and nucleotide binding but had minimal effect on the NM23-H2 crystal structure. On the basis of these data and molecular modeling studies, we have proposed a stepwise trapping-out of the NHE III(1) region in a single-stranded form, thus allowing single-stranded transcription factors to bind and activate c-myc transcription. Furthermore, this model provides a rationale for how the stabilization of the G-quadruplex or i-motif structures formed within the c-myc gene promoter region can inhibit NM23-H2 from activating c-myc gene expression.

SUBMITTER: Dexheimer TS 

PROVIDER: S-EPMC2891668 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

altmetric image

Publications

NM23-H2 may play an indirect role in transcriptional activation of c-myc gene expression but does not cleave the nuclease hypersensitive element III(1).

Dexheimer Thomas S TS   Carey Steven S SS   Zuohe Song S   Gokhale Vijay M VM   Hu Xiaohui X   Murata Lauren B LB   Maes Estelle M EM   Weichsel Andrzej A   Sun Daekyu D   Meuillet Emmanuelle J EJ   Montfort William R WR   Hurley Laurence H LH  

Molecular cancer therapeutics 20090512 5


The formation of G-quadruplex structures within the nuclease hypersensitive element (NHE) III(1) region of the c-myc promoter and the ability of these structures to repress c-myc transcription have been well established. However, just how these extremely stable DNA secondary structures are transformed to activate c-myc transcription is still unknown. NM23-H2/nucleoside diphosphate kinase B has been recognized as an activator of c-myc transcription via interactions with the NHE III(1) region of t  ...[more]

Similar Datasets

| S-EPMC2615625 | biostudies-literature
| S-EPMC4538829 | biostudies-literature
| S-EPMC3317485 | biostudies-literature
| S-EPMC2000435 | biostudies-literature
| S-EPMC6183060 | biostudies-literature
| S-EPMC2964402 | biostudies-literature
| S-EPMC3962447 | biostudies-literature
| S-EPMC1538576 | biostudies-literature
| S-EPMC3020117 | biostudies-literature
2014-08-04 | GSE40194 | GEO