Page 125 - CSIR-IGIB Annual Report 2020-21

Non-duplex DNA controls Telomerase in cancer Telomeres impact cancer-immune cell crosstalk
Controlling reactivated telomerase in cancer: Non- Telomere-dependent regulation of the
duplex structure plays a key role in epigenetic interleukin-1 receptor modulates immune cell
regulation of the telomerase promoter. infiltration in cancer. TRF2 is a known component
Reactivation of telomerase is hallmark of many of the mammalian Shelterin complex and is critical
cancers. Telomerase is generally repressed in for telomere maintenance. Interestingly, recent
adult normal cells and is found to be activated in findings suggest that TRF2 can associate with DNA
~90% of cancers. However, underlying outside telomeres including several gene
mechanisms that trigger reactivation have promoters. Our earlier work showed that TRF2 can
remained poorly understood. Our findings show modulate transcription by inducing local
that DNA secondary structure G-quadruplex epigenetics in a telomere length-dependent
regulates the epigenetic state of the telomerase manner. We found evidence that TRF2 associates
promoter, and thereby expression of telomerase with G-quadruplexes at the IL1R1 (Interleukin 1
remains under control. The relevance of this Receptor Type 1) promoter. TRF2-dependent
mechanism is underscored through two clinical activation of IL1R1 is through recruitment of
mutations – found in high frequency in a large H3K27ac by the p300 histone acetyltransferase. As
number of glioblastoma and melanoma patients - a consequence, cells with high TRF2 have
that disrupt G-quadruplex formation. Ligand- enhanced sensitivity to the pro-inflammatory
induced re-stabilization of the promoter G- cytokine IL1 beta, resulting in activation of NF
quadruplex restored the epigenetic state and re- kappa B targets IL6, IL8 and TNFα. We further
suppressed telomerase in cancer cells, show how TRF2 mediated upregulation of IL1R1 in
substantiating the newly revealed mechanistic cancer cells is causal for recruitment and
understanding. Overall, this brings forth two novel maintenance of tumour-associated macrophages
points. First, it shows the use of G-quadruplex- in the tumour micro-environment and its
stabilizing ligands in regulating hTERT expression connection to telomere length of cancer cells.
via restoration of the transcription factor binding Taken together, these findings for the first time
site in neoplastic, hTERT-reactivated cancer cells. point out: (a) how telomeres impact immune cells
Second, it shows the possibility for the like macrophages in the molecular crosstalk with
development of novel G-quadruplex targeting cancer cells and (b) the role of the G-quadruplex
epigenetic drugs that may work in telomerase structure in regulation of the interleukin receptor
regulation. that could be exploited for therapeutic benefit.

Publications
Extra-telomeric impact of telomeres: Emerging molecular connections in pluripotency or stemness. Vinayagamurthy S,
Ganguly A, Chowdhury S. J Biol Chem. 2020 Jul 24;295(30):10245-10254.

Non-duplex G-quadruplex DNA structure: A developing story from predicted sequences to DNA structure-dependent
epigenetics and beyond. Sengupta A, Roy SS, Chowdhury S. Acc Chem Res. 2021 Jan 5;54(1):46-56.

Emerging molecular connections between NM23 proteins, telomeres and telomere-associated factors: Implications in
cancer metastasis and ageing. Sharma S, Sengupta A, Chowdhury S. Int J Mol Sci. 2021 Mar 27;22(7):3457.

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