G-Quadruplex Structures Formed at the HOX11 Breakpoint Region Contribute to Its Fragility during t(10;14) Translocation in T-Cell Leukemia

Nambiar, Mridula and Srivastava, Mrinal and Gopalakrishnan, Vidya and Sankaran, Sritha K and Raghavan, Sathees C (2013) G-Quadruplex Structures Formed at the HOX11 Breakpoint Region Contribute to Its Fragility during t(10;14) Translocation in T-Cell Leukemia. In: MOLECULAR AND CELLULAR BIOLOGY, 33 (21). pp. 4266-4281.

PDF Mol_Cell_Biol_33-21_4266_2013.pdf - Published Version Restricted to Registered users only Download (4MB) | Request a copy

Abstract

The t(10;14) translocation involving the HOX11 gene is found in several T-cell leukemia patients. Previous efforts to determine the causes of HOX11 fragility were not successful. The role of non-B DNA structures is increasingly becoming an important cause of genomic instability. In the present study, bioinformatics analysis revealed two G-quadruplex-forming motifs at the HOX11 breakpoint cluster. Gel shift assays showed formation of both intra- and intermolecular G-quadruplexes, the latter being more predominant. The structure formation was dependent on four stretches of guanines, as revealed by mutagenesis. Circular dichroism analysis identified parallel conformations for both quadruplexes. The non-B DNA structure could block polymerization during replication on a plasmid, resulting in consistent K K+-dependent pause sites, which were abolished upon mutation of G-motifs, thereby demonstrating the role of the stretches of guanines even on double-stranded DNA. Extrachromosomal assays showed that the G-quadruplex motifs could block transcription, leading to reduced expression of green fluorescent protein (GFP) within cells. More importantly, sodium bisulfite modification assay showed the single-stranded character at regions I and II of HOX11 in the genome. Thus, our findings suggest the occurrence of G-quadruplex structures at the HOX11 breakpoint region, which could explain its fragility during the t(10;14) translocation.

Item Type:	Journal Article
Publication:	MOLECULAR AND CELLULAR BIOLOGY
Publisher:	AMER SOC MICROBIOLOGY
Additional Information:	copyright for this article belongs to AMER SOC MICROBIOLOGY
Department/Centre:	Division of Biological Sciences > Biochemistry
Date Deposited:	11 Nov 2013 11:35
Last Modified:	11 Nov 2013 11:35
URI:	http://eprints.iisc.ac.in/id/eprint/47738

Actions (login required)

View Item