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HMGB1 binds to the KRAS promoter G-quadruplex: a new player in oncogene transcriptional regulation?

ABSTRACT: This communication reports on a possible distinct role of HMGB1 protein. Biophysical studies revealed that HMGB1 binds and stabilizes the G-quadruplex of the KRAS promoter element that is responsible for most of the transcriptional activity. Biological data showed that inhibition of HMGB1 increases KRAS expression. These results suggest that HMGB1 could play a role in the gene transcriptional regulation via the functional recognition of the G-quadruplex.

SUBMITTER: Amato J

PROVIDER: S-EPMC6234227 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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HMGB1 binds to the KRAS promoter G-quadruplex: a new player in oncogene transcriptional regulation?

Amato Jussara J Madanayake Thushara W TW Iaccarino Nunzia N Novellino Ettore E Randazzo Antonio A Hurley Laurence H LH Pagano Bruno B

Chemical communications (Cambridge, England) 20180801 68

This communication reports on a possible distinct role of HMGB1 protein. Biophysical studies revealed that HMGB1 binds and stabilizes the G-quadruplex of the KRAS promoter element that is responsible for most of the transcriptional activity. Biological data showed that inhibition of HMGB1 increases KRAS expression. These results suggest that HMGB1 could play a role in the gene transcriptional regulation via the functional recognition of the G-quadruplex. ...[more]

PMID: 30079419

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Project description:In human and mouse, the promoter of the KRAS gene contains a nuclease hypersensitive polypurine-polypyrimidine element (NHPPE) that is essential for transcription. An interesting feature of the polypurine G-rich strand of NHPPE is its ability to assume an unusual DNA structure that, according to circular dichroism (CD) and DMS footprinting experiments, is attributed to an intramolecular parallel G-quadruplex, consisting of three G-tetrads and three loops. The human and mouse KRAS NHPPE G-rich strands display melting temperature of 64 and 73 degrees C, respectively, as well as a K+-dependent capacity to arrest DNA polymerase. Photocleavage and CD experiments showed that the cationic porphyrin TMPyP4 stacks to the external G-tetrads of the KRAS quadruplexes, increasing the T(m) by approximately 20 degrees C. These findings raise the intriguing question that the G-quadruplex formed within the NHPPE of KRAS may be involved in the regulation of transcription. Indeed, transfection experiments showed that the activity of the mouse KRAS promoter is reduced to 20% of control, in the presence of the quadruplex-stabilizing TMPyP4. In addition, we found that G-rich oligonucleotides mimicking the KRAS quadruplex, but not the corresponding 4-base mutant sequences or oligonucleotides forming quadruplexes with different structures, competed with the NHPPE duplex for binding to nuclear proteins. When vector pKRS-413, containing CAT driven by the mouse KRAS promoter, and KRAS quadruplex oligonucleotides were co-transfected in 293 cells, the expression of CAT was found to be downregulated to 40% of the control. On the basis of these data, we propose that the NHPPE of KRAS exists in equilibrium between a double-stranded form favouring transcription and a folded quadruplex form, which instead inhibits transcription. Such a mechanism, which is probably adopted by other growth-related genes, provides useful hints for the rational design of anticancer drugs against the KRAS oncogene.

Dataset Information

HMGB1 binds to the KRAS promoter G-quadruplex: a new player in oncogene transcriptional regulation?

Publications

HMGB1 binds to the KRAS promoter G-quadruplex: a new player in oncogene transcriptional regulation?

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