The lncRNA CONCR is upregulated in multiple tumor types and is essential for sister chromatid cohesion.
Major finding: The lncRNA CONCR is upregulated in multiple tumor types and is essential for sister chromatid cohesion.
Mechanism: CONCR is activated by MYC and directly regulates the activity of the helicase DDX11.
Impact: LncRNAs may directly act during cell division to maintain genome stability.
Long noncoding RNAs (lncRNA) have been linked to diverse cellular processes, including those involved in cancer, but only a small proportion of lncRNAs have been functionally characterized. To discover lncRNAs potentially involved in cell-cycle progression, Marchese and colleagues explored lncRNAs differentially expressed in p53-null cells and observed upregulation of a noncoding, antisense, nonoverlapping transcript of the gene encoding DEAD/H-box helicase 11 (DDX11), a protein involved in DNA replication and sister chromatid cohesion. The lncRNA was ultimately named cohesion regulator noncoding RNA (CONCR). Although CONCR was upregulated in response to p53 deletion, p53 did not bind to the CONCR promoter. However, MYC bound to the CONCR promoter, resulting in CONCR upregulation. CONCR was upregulated in the majority of human tumors, and in colon cancer xenografts, CONCR depletion reduced tumor growth. In vitro, depletion of CONCR resulted in reduced cell proliferation, increased apoptosis, enhanced G0/G1 cell-cycle arrest, and downregulation of genes involved in the G1 to S phase transition, indicating a role for CONCR in cell division and survival. CONCR was tightly regulated across the cell cycle, exhibiting periodic expression with peak expression occurring in the mid-late G1 phase of the cell cycle, supporting a role in DNA replication and the G1/S transition. Depletion of CONCR or DDX11 resulted in loss of sister chromatin cohesion, resulting in “loosely paired” chromatids and suggesting a functional relationship between CONCR and DDX11. CONCR interacted with the DDX11 protein and the complex bound replicating regions of DNA in a CONCR-dependent manner. Moreover, CONCR enhanced the ATPase activity of DDX11 in vitro. Taken together, these findings demonstrate that CONCR regulates DDX11 activity to maintain sister chromatin adhesion, cell-cycle progression, and cell survival, implicating lncRNAs in cell division and genome instability and suggesting the possibility of targeting these lncRNAs in cancer.
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