c-Myc quadruplex-forming sequence Pu-27 induces extensive damage in both telomeric and non-telomeric regions of DNA. Islam, M. A., Thomas, S. D, Murty, V. V, Sedoris, K. J, & Miller, D. M The Journal of biological chemistry, January, 2014.
Paper doi abstract bibtex ABSTRACT Quadruplex-forming DNA sequences are present throughout the eukaryotic genome, including in telomeric DNA. We have shown c-myc promoter quadruplex-forming sequence, Pu-27, selectively kills transformed cells (Sedoris et al., 2012). In this study, we show that Pu-27 induces profound DNA damage resulting in striking chromosomal abnormalities in the form of chromatid or chromosomal breaks, radial formation, telomeric DNA loss which induces γ-H2AX in U937 cells. Pu-27 down regulates telomeric shelterin proteins, DNA damage response mediators (RAD17 and RAD50), double strand break (DSB) repair molecule 53BP1, G2 checkpoint regulators (CHK1 and CHK2) and anti-apoptosis gene survivin. Interestingly, there are no changes of DNA repair molecules H2AX, BRCA1 and the telomere maintenance gene, hTERT. delta-B-U937, where U937 cells stably transfected with deleted basic-domain of TRF2 is partially sensitive to Pu-27 but exhibits no changes in expression of shelterin proteins. However, there is an up-regulation of CHK1, CHK2, H2AX, BRCA1, and survivin. TIF (Telomere-dysfunction Induced Foci) assay revealed co-association of TRF1with gamma-H2AX in ATM deficient cells which are differentially sensitive to Pu-27 than ATM proficient cells. Alt (Alternating Lengthening of Telomere) cells are relatively resistant to Pu-27 but no significant changes of telomerase activity in both Alt and non-Alt cells. Lastly, we show this Pu-27 mediated sensitivity is P53 independent. The data therefore support two conclusions. Firstly, Pu-27 induces DNA damage within both telomeric and non-telomeric regions of the genome. Secondly, Pu-27 mediated telomeric damage is due, at least in part, to compromise of the telomeric shelterin protein complex.
@article{Islam2014,
title = {c-{Myc} quadruplex-forming sequence {Pu}-27 induces extensive damage in both telomeric and non-telomeric regions of {DNA}.},
issn = {1083-351X},
url = {http://www.ncbi.nlm.nih.gov/pubmed/24464582},
doi = {10.1074/jbc.m113.505073},
abstract = {ABSTRACT Quadruplex-forming DNA sequences are present throughout the eukaryotic genome, including in telomeric DNA. We have shown c-myc promoter quadruplex-forming sequence, Pu-27, selectively kills transformed cells (Sedoris et al., 2012). In this study, we show that Pu-27 induces profound DNA damage resulting in striking chromosomal abnormalities in the form of chromatid or chromosomal breaks, radial formation, telomeric DNA loss which induces γ-H2AX in U937 cells. Pu-27 down regulates telomeric shelterin proteins, DNA damage response mediators (RAD17 and RAD50), double strand break (DSB) repair molecule 53BP1, G2 checkpoint regulators (CHK1 and CHK2) and anti-apoptosis gene survivin. Interestingly, there are no changes of DNA repair molecules H2AX, BRCA1 and the telomere maintenance gene, hTERT. delta-B-U937, where U937 cells stably transfected with deleted basic-domain of TRF2 is partially sensitive to Pu-27 but exhibits no changes in expression of shelterin proteins. However, there is an up-regulation of CHK1, CHK2, H2AX, BRCA1, and survivin. TIF (Telomere-dysfunction Induced Foci) assay revealed co-association of TRF1with gamma-H2AX in ATM deficient cells which are differentially sensitive to Pu-27 than ATM proficient cells. Alt (Alternating Lengthening of Telomere) cells are relatively resistant to Pu-27 but no significant changes of telomerase activity in both Alt and non-Alt cells. Lastly, we show this Pu-27 mediated sensitivity is P53 independent. The data therefore support two conclusions. Firstly, Pu-27 induces DNA damage within both telomeric and non-telomeric regions of the genome. Secondly, Pu-27 mediated telomeric damage is due, at least in part, to compromise of the telomeric shelterin protein complex.},
journal = {The Journal of biological chemistry},
author = {Islam, Md Ashraful and Thomas, Shelia D and Murty, Vundavalli V and Sedoris, Kara J and Miller, Donald M},
month = jan,
year = {2014},
pmid = {24464582},
keywords = {\#nosource, alt, cell death, complex, dna damage, g-quadruplex, myc, shelterin, survivin, telomeres},
}
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