Long noncoding RNA NIHCOLE promotes ligation efficiency of DNA double-strand breaks in hepatocellular carcinoma

Juan P. Unfried*, Mikel Marín-Baquero, Ángel Rivera-Calzada, Nerea Razquin, Eva M. Martín-Cuevas, Sara de Bragança, Clara Aicart-Ramos, Christopher McCoy, Laura Prats-Mari, Raquel Arribas-Bosacoma, Linda Lee, Stefano Caruso, Jessica Zucman-Rossi, Bruno Sangro, Gareth Williams, Fernando Moreno-Herrero, Oscar Llorca, Susan P. Lees-Miller, Puri Fortes

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Long noncoding RNAs (lncRNA) are emerging as key players in cancer as parts of poorly understood molecular mechanisms. Here, we investigated lncRNAs that play a role in hepatocellular carcinoma (HCC) and identified NIHCOLE, a novel lncRNA induced in HCC with oncogenic potential and a role in the ligation efficiency of DNA double-stranded breaks (DSB). NIHCOLE expression was associated with poor prognosis and survival of HCC patients. Depletion of NIHCOLE from HCC cells led to impaired proliferation and increased apoptosis. NIHCOLE deficiency led to accumulation of DNA damage due to a specific decrease in the activity of the nonhomologous end-joining (NHEJ) pathway of DSB repair. DNA damage induction in NIHCOLE-depleted cells further decreased HCC cell growth. NIHCOLE was associated with DSB markers and recruited several molecules of the Ku70/Ku80 heterodimer. Further, NIHCOLE putative structural domains supported stable multimeric complexes formed by several NHEJ factors including Ku70/80, APLF, XRCC4, and DNA ligase IV. NHEJ reconstitution assays showed that NIHCOLE promoted the ligation efficiency of blunt-ended DSBs. Collectively, these data show that NIHCOLE serves as a scaffold and facilitator of NHEJ machinery and confers an advantage to HCC cells, which could be exploited as a targetable vulnerability.

Original languageEnglish
Pages (from-to)4910-4925
Number of pages16
JournalCancer Research
Issue number19
Publication statusPublished - 1 Oct 2021


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