NDLI: MGMT DNA repair gene promoter/enhancer haplotypes alter transcription factor binding and gene expression

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MGMT DNA repair gene promoter/enhancer haplotypes alter transcription factor binding and gene expression

Content Provider	Springer Nature Link
Author	Xu, Meixiang Cross, Courtney E. Speidel, Jordan T. Abdel Rahman, Sherif Z.
Copyright Year	2016
Abstract	The O$^{6}$-methylguanine-DNA methyltransferase (MGMT) protein removes O$^{6}$-alkyl-guanine adducts from DNA. MGMT expression can thus alter the sensitivity of cells and tissues to environmental and chemotherapeutic alkylating agents. Previously, we defined the haplotype structure encompassing single nucleotide polymorphisms (SNPs) in the MGMT promoter/enhancer (P/E) region and found that haplotypes, rather than individual SNPs, alter MGMT promoter activity. The exact mechanism(s) by which these haplotypes exert their effect on MGMT promoter activity is currently unknown, but we noted that many of the SNPs comprising the MGMT P/E haplotypes are located within or in close proximity to putative transcription factor binding sites. Thus, these haplotypes could potentially affect transcription factor binding and, subsequently, alter MGMT promoter activity.In this study, we test the hypothesis that MGMT P/E haplotypes affect MGMT promoter activity by altering transcription factor (TF) binding to the P/E region. We used a promoter binding TF profiling array and a reporter assay to evaluate the effect of different P/E haplotypes on TF binding and MGMT expression, respectively.Our data revealed a significant difference in TF binding profiles between the different haplotypes evaluated. We identified TFs that consistently showed significant haplotype-dependent binding alterations (p ≤ 0.01) and revealed their role in regulating MGMT expression using siRNAs and a dual-luciferase reporter assay system.The data generated support our hypothesis that promoter haplotypes alter the binding of TFs to the MGMT P/E and, subsequently, affect their regulatory function on MGMT promoter activity and expression level.
Starting Page	435
Ending Page	447
Page Count	13
File Format	PDF
ISSN	22113428
Journal	Cellular Oncology
Volume Number	39
Issue Number	5
e-ISSN	22113436
Language	English
Publisher	Springer Netherlands
Publisher Date	2016-06-15
Publisher Institution	International Society for Cellular Oncology
Publisher Place	Dordrecht
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	MGMT P/E haplotypes Transcription factor binding siRNA regulation Promoter activity Cancer Research Biomedicine Pathology Oncology
Content Type	Text
Resource Type	Article
Subject	Cancer Research Molecular Medicine Oncology

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MGMT DNA repair gene promoter/enhancer haplotypes alter transcription factor binding and gene expression