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The N-Myc-Responsive LncRNA MILIP Promotes Non-Homologous DNA End Joining to Alleviate Genotoxic Stress in Human Neuroblastoma

ABSTRACT: lncRNAMILIP promotes the NHEJ pathway through facilitating Ku70-Ku80 heterodimerization and is involved in the resistance to DNA-damaging therapeutics in neuroblastoma cells.

ORGANISM(S): Homo Sapiens

SUBMITTER: Xudong Zhang

PROVIDER: PXD033372 | iProX | Fri Apr 22 00:00:00 BST 2022

REPOSITORIES: iProX

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The N-Myc-responsive lncRNA MILIP promotes DNA double-strand break repair through non-homologous end joining.

Wang Pei Lin PL Teng Liu L Feng Yu Chen YC Yue Yi Meng YM Han Man Man MM Yan Qianqian Q Ye Kaihong K Tang Cai Xia CX Zhang Sheng Nan SN Fei Qi Teng T Zhao Xiao Hong XH La Ting T Zhang Yuan Yuan YY Li Jin Ming JM Hu Bin B Xu Dengfei D Cang Shundong S Wang Li L Jin Lei L Thorne Rick F RF Zhang Yuwei Y Liu Tao T Zhang Xu Dong XD

Proceedings of the National Academy of Sciences of the United States of America 20221129 49

The protooncoprotein N-Myc, which is overexpressed in approximately 25% of neuroblastomas as the consequence of <i>MYCN</i> gene amplification, has long been postulated to regulate DNA double-strand break (DSB) repair in neuroblastoma cells, but experimental evidence of this function is presently scant. Here, we show that N-Myc transcriptionally activates the long noncoding RNA MILIP to promote nonhomologous end-joining (NHEJ) DNA repair through facilitating Ku70-Ku80 heterodimerization in neuro ...[more]

PMID: 36445966

Similar Datasets

The N-Myc-responsive lncRNA MILIP promotes DNA double-strand break repair through non-homologous end joining.

Project description:The protooncoprotein N-Myc, which is overexpressed in approximately 25% of neuroblastomas as the consequence of MYCN gene amplification, has long been postulated to regulate DNA double-strand break (DSB) repair in neuroblastoma cells, but experimental evidence of this function is presently scant. Here, we show that N-Myc transcriptionally activates the long noncoding RNA MILIP to promote nonhomologous end-joining (NHEJ) DNA repair through facilitating Ku70-Ku80 heterodimerization in neuroblastoma cells. High MILIP expression was associated with poor outcome and appeared as an independent prognostic factor in neuroblastoma patients. Knockdown of MILIP reduced neuroblastoma cell viability through the induction of apoptosis and inhibition of proliferation, retarded neuroblastoma xenograft growth, and sensitized neuroblastoma cells to DNA-damaging therapeutics. The effect of MILIP knockdown was associated with the accumulation of DNA DSBs in neuroblastoma cells largely due to decreased activity of the NHEJ DNA repair pathway. Mechanistical investigations revealed that binding of MILIP to Ku70 and Ku80 increased their heterodimerization, and this was required for MILIP-mediated promotion of NHEJ DNA repair. Disrupting the interaction between MILIP and Ku70 or Ku80 increased DNA DSBs and reduced cell viability with therapeutic potential revealed where targeting MILIP using Gapmers cooperated with the DNA-damaging drug cisplatin to inhibit neuroblastoma growth in vivo. Collectively, our findings identify MILIP as an N-Myc downstream effector critical for activation of the NHEJ DNA repair pathway in neuroblastoma cells, with practical implications of MILIP targeting, alone and in combination with DNA-damaging therapeutics, for neuroblastoma treatment.

| S-EPMC9894261 | biostudies-literature

RNF4 sustains Myc-driven tumorigenesis by facilitating DNA replication

Project description:RNF4 sustains Myc-driven tumorigenesis by facilitating DNA replication

2022-08-16 | MSV000090142 | MassIVE

Androgen-Responsive Oncogenic lncRNA RP11-1023L17.1 Enhances c-Myc Protein Stability in Prostate Cancer.

Project description:Long noncoding RNAs (lncRNAs) have been found as novel participants in the pathophysiology of prostate cancer (PCa), which is predominantly regulated by androgen and its receptor. The biological function of androgen-responsive lncRNAs remains poorly understood. Here, we identified that lncRNA RP11-1023L17.1, which is highly expressed in PCa. RP11-1023L17.1 expression, can be directly repressed by the androgen receptor in PCa cells. RP11-1023L17.1 depletion inhibited the proliferation, migration, and cell cycle progression, and promoted the apoptosis of PCa cells, indicating that RP11-1023L17.1 acts as an oncogene in PCa cells. Microarray results revealed that RP11-1023L17.1 depletion downregulated the c-Myc transcription signature in PCa cells. RP11-1023L17.1 depletion-induced cellular phenotypes can be overcome by ectopically overexpressed c-Myc. Mechanistically, RP11-1023L17.1 represses FBXO32 mRNA expression, thereby enhancing c-Myc protein stability by blocking FBXO32-mediated c-Myc degradation. Our findings reveal the previously unrecognized roles of RP11-1023L17.1 in c-Myc-dependent PCa tumorigenesis.

| S-EPMC9603324 | biostudies-literature

Divergent lncRNA MYMLR regulates MYC by eliciting DNA looping and promoter-enhancer interaction.

Project description:Long non-coding RNAs (lncRNAs) function in a wide range of processes by diverse mechanisms, though their roles in regulation of oncogenes and/or tumor suppressors remain rather elusive. We performed a global search for lncRNAs affecting MYC activity using a systems biology-based approach with a K supercomputer and the GIMLET algorism based on local distance correlations. Consequently, MYMLR was identified and experimentally shown to maintain MYC transcriptional activity and cell cycle progression despite the low levels of expression. A proteomic search for MYMLR-binding proteins identified PCBP2, while it was also found that MYMLR places a 557-kb upstream enhancer region in the proximity of the MYC promoter in cooperation with PCBP2. These findings implicate a crucial role for MYMLR in regulation of the archetypical oncogene MYC and warrant future studies regarding the involvement of low copy number lncRNAs in regulation of other crucial oncogenes and tumor suppressor genes.

| S-EPMC6717891 | biostudies-literature

Oligonucleotide Binding to Non-B-DNA in MYC.

Project description:MYC, originally named c-myc, is an oncogene deregulated in many different forms of cancer. Translocation of the MYC gene to an immunoglobulin gene leads to an overexpression and the development of Burkitt's lymphoma (BL). Sporadic BL constitutes one subgroup where one of the translocation sites is located at the 5'-vicinity of the two major MYC promoters P₁ and P₂. A non-B-DNA forming sequence within this region has been reported with the ability to form an intramolecular triplex (H-DNA) or a G-quadruplex. We have examined triplex formation at this site first by using a 17 bp triplex-forming oligonucleotide (TFO) and a double strand DNA (dsDNA) target corresponding to the MYC sequence. An antiparallel purine-motif triplex was detected using electrophoretic mobility shift assay. Furthermore, we probed for H-DNA formation using the BQQ-OP based triplex-specific cleavage assay, which indicated the formation of the structure in the supercoiled plasmid containing the corresponding region of the MYC promoter. Targeting non-B-DNA structures has therapeutic potential; therefore, we investigated their influence on strand-invasion of anti-gene oligonucleotides (ON)s. We show that in vitro, non-B-DNA formation at the vicinity of the ON target site facilitates dsDNA strand-invasion of the anti-gene ONs.

| S-EPMC6429085 | biostudies-literature

LncRNA-MIF, a c-Myc-activated long non-coding RNA, suppresses glycolysis by promoting Fbxw7-mediated c-Myc degradation.

Project description:The c-Myc proto-oncogene is activated in more than half of all human cancers. However, the precise regulation of c-Myc protein stability is unknown. Here, we show that the lncRNA-MIF (c-Myc inhibitory factor), a c-Myc-induced long non-coding RNA, is a competing endogenous RNA for miR-586 and attenuates the inhibitory effect of miR-586 on Fbxw7, an E3 ligase for c-Myc, leading to increased Fbxw7 expression and subsequent c-Myc degradation. Our data reveal the existence of a feedback loop between c-Myc and lncRNA-MIF, through which c-Myc protein stability is finely controlled. Additionally, we show that the lncRNA-MIF inhibits aerobic glycolysis and tumorigenesis by suppressing c-Myc and miR-586.

| S-EPMC4967955 | biostudies-literature

Promoting axon regeneration by enhancing the non-coding function of the injury-responsive coding gene Gpr151

Project description:Gene expression profiling in response to nerve injury has been mainly focused on protein functions of coding genes to understand mechanisms of axon regeneration and to identify targets of potential therapeutics for nerve repair. However, the protein functions of several highly injury-induced genes including Gpr151 for regulating the regenerative ability remain unclear. Here we present an alternative approach focused on non-coding functions of the coding genes, which led to the identification of the non-coding function of Gpr151 RNA interacting with RNA-binding proteins such as CSDE1. Gpr151 promotes axon regeneration by the function of its 5’- untranslated region (5’UTR) and expression of an engineered form of the 5’UTR improves regenerative capacity in vitro and in vivo in both sciatic nerve and optic nerve injury models. Our data suggest that searching injury-induced coding genes potentially functioning by their non-coding regions is required for the RNA-based gene therapy for improving axon regeneration.

2021-07-01 | GSE179145 | GEO

Chemotherapy With DNA Damaging Agents In Colorectal Cancer

Project description:Chemotherapy Treatment alone with DNA damaging drugs might be as effective as chemotherapy combined with surgery in colorectal cancer (CRC) avoiding surgery complications.

| 2114543 | ecrin-mdr-crc

EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation

Project description:Efforts to therapeutically target EZH2 have generally focused on inhibition of its methyltransferase activity, although it remains less clear whether this is the central mechanism whereby EZH2 promotes cancer. We demonstrate that EZH2 directly interacts with both MYC family oncoproteins, MYC and MYCN, and promotes their stabilization in a methyltransferase-independent manner. By competing against the SCFFBW7 ubiquitin ligase to bind MYC and MYCN, EZH2 counteracted FBW7-mediated MYC(N) polyubiquitination and proteasomal degradation. Depletion, but not enzymatic inhibition, of EZH2 induced robust MYC(N) degradation and inhibited tumor cell growth in MYC(N) driven neuroblastoma and small cell lung cancer. These findings unveil the MYC family proteins as global EZH2 oncogenic effectors and EZH2 pharmacologic degraders as potential MYC(N) targeted cancer therapeutics, pointing out that MYC(N) driven cancers may develop inherent resistance to the canonical EZH2 enzymatic inhibitors currently in clinical development.

2022-02-17 | PXD029652 | Pride

Vanguard is a glucose deprivation-responsive long non-coding RNA essential for chromatin remodeling-reliant DNA repair

Project description:Glucose metabolism contributes to DNA damage response (DDR) pathways by regulating chromatin remodeling, double-strand break (DSB) repair, and redox homeostasis, although the underlying mechanisms are not fully established. Here, we reveal a previously uncharacterized long noncoding RNA we call Vanguard which acts to promote HMGB1-dependent DNA repair in association with changes in global chromatin accessibility. Vanguard expression is maintained in cancer cells by SP1-dependent transcription according to glucose availability and cellular ATP levels. Vanguard promotes complex formation between HMGB1 and HDAC1, with the resulting deacetylation of HMGB1 serving to maintain its nuclear localization and DSB repair function. However, Vanguard downregulation under glucose limiting conditions promotes HMGB1 translocation from the nucleus, increasing DNA damage and compromising cancer cell growth and viability. Moreover, Vanguard silencing increases the effectiveness of poly (ADP-ribose) polymerase inhibitors (PARPi) against breast cancer cells with wildtype breast cancer gene-1 status, suggesting Vanguard as a potential therapeutic target.

2025-02-09 | GSE197519 | GEO

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