Maintenance of a Stable Karyotype Depends on Action of a Long Noncoding RNA

A long noncoding RNA (lncRNA) regulates cellular genomic stability by sequestering the PUMILIO proteins, which would otherwise drive chromosomal instability by repressing mitotic, DNA repair, and DNA replication factors.

Long noncoding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides. This somewhat arbitrary limit distinguishes lncRNAs from small regulatory RNAs such as microRNAs (miRNAs), short interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), and other short RNAs. LncRNAs have been found to be involved in numerous biological roles including imprinting, epigenetic gene regulation, cell cycle and apoptosis, and metastasis and prognosis in solid tumors. Most lncRNAs are expressed only in a few cells rather than whole tissues, or they are expressed at very low levels, making them difficult to study.

Investigators at the University of Texas Southwestern Medical Center (Dallas, USA) described the initial functional analysis of a poorly characterized human lncRNA (LINC00657) that was induced after DNA damage. The investigators called this class of RNA “noncoding RNA activated by DNA damage”, or NORAD.

They reported in the December 24, 2015, online edition of the journal Cell that NORAD was highly conserved and abundant, with expression levels of approximately 500–1,000 copies per cell. Unexpectedly, inactivation of NORAD was found to trigger the dramatic development of aneuploidy in previously karyotypically stable cell lines.

The investigators showed that NORAD maintained genomic stability by sequestering the PUMILIO proteins PUM1 and PUM2 (pumilio RNA binding family member 1 and pumilio RNA binding family member 2), which repressed the stability and translation of mRNAs to which they bound. In the absence of NORAD, PUMILIO proteins drove chromosomal instability by repressing mitotic, DNA repair, and DNA replication factors.

"In the absence of the NORAD RNA, the number of chromosomes in cells becomes highly abnormal," said senior author Dr. Joshua Mendell, professor of molecular biology at the University of Texas Southwestern Medical Center. "This is an entirely new function for a noncoding RNA and may have implications in cancer biology since genomic instability is a hallmark of tumor cells."

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University of Texas Southwestern Medical Center