RNAi-Mediated Loss of the NEIL3 DNA Glycosylase Leads to Deregulation of the TERRA Long
Non-coding RNAs in Glioblastoma Cell Lines

Glioblastoma (GBM) is the most aggressive type of brain tumor. Despite systemic treatment, GBM
remains an incurable cancer with a median survival of only 15 months. Thus, urgent novel strategy is
needed to prevent treatment resistance in GBM. Reactive oxygen species (ROS) generated as by-
products of cellular metabolism or upon exposure to DNA genotoxic agents, induce guanine
oxidation lesions. NEIL3 encodes a DNA glycosylase involved in the base excision repair (BER)
pathway that repairs guanine oxidation lesions. The latest are prone to occur at telomeres, the
physical ends of our chromosomes, which are composed of TTAGGG repeats. The reparation of such
lesions is tremendously important for telomere integrety.
Our team demonstrated that RNAi-mediated depletion of NEIL3 led to telomere attrition and
deregulation of Telomeric Repeat-containing RNA (TERRA) long non-coding RNA (lncRNA) expression in the GBM stem-like cell (GSC) line NCH644. In addition, our team showed that loss of NEIL3 in these
cells led to the downregulation of TRF1, a component of the shelterin complex protecting telomere
ends. As a step to generalize the role of NEIL3 in maintaining TERRA integrity in GBM. We examined
whether TERRA deregulation is also observed upon depletion of NEIL3 in U87 GBM cells, indeed,
NEIL3 depletion led to TERRA upregulation at all the telomeres studied in U87 cells.
In addition, the mRNA levels of TERF1 were downregulated in NEIL3-depleted U87 cells. Since the
shelterin components TRF1 and TRF2 suppress TERRA abundance, our results suggest that NEIL3
affects TERRA expression through its modulation of TERF1 expression.
Keywords: NEIL3 DNA Glycosylase; TRF1; TERRA Long Non-coding RNAs; Telomere; Glioblastoma.

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