Cell cycle regulation by long non-coding RNAs

Abstract

The mammalian cell cycle is precisely controlled by cyclin-dependent kinases (CDKs) and related pathways such as the RB and p53 pathways. Recent research on long non-coding RNAs (lncRNAs) indicates that many lncRNAs are involved in the regulation of critical cell cycle regulators such as the cyclins, CDKs, CDK inhibitors, pRB, and p53. These lncRNAs act as epigenetic regulators, transcription factor regulators, post-transcription regulators, and protein scaffolds. These cell cycle-regulated lncRNAs mainly control cellular levels of cell cycle regulators via various mechanisms, and may provide diversity and reliability to the general cell cycle. Interestingly, several lncRNAs are induced by DNA damage and participate in cell cycle arrest or induction of apoptosis as DNA damage responses. Therefore, deregulations of these cell cycle regulatory lncRNAs may be involved in tumorigenesis, and they are novel candidate molecular targets for cancer therapy and diagnosis.

Fig. 1

Outline of cell cycle control and involvement of lncRNAs. The mammalian cell cycle is controlled by cyclin-dependent kinases (CDKs) and their related pathways. CDKs are activated via binding to their selected cyclins in specific phases of the cell cycle, following which they phosphorylate their target proteins. The CDK inhibitors (CKIs) negatively regulate the activities of CDKs and control the cell cycle. pRB regulates G1/S progression. The p53 pathway plays a role in DNA damage response as a gatekeeper of the genome. Several lncRNAs control the expression of cyclins-CDKs, CKIs, pRB and p53, and participate in cell cycle regulation. Some of these lncRNAs are induced by DNA damage and inhibit cell cycle progression by regulating these cell cycle regulators

Fig. 2

Model showing the proposed mechanisms of lncRNA-mediated regulation of cyclin D1 (a) and CDK6 (b) induced by DNA damage. a DNA damage induces the transcription of ncRNA _CCND1 from the promoter region of the cyclin D1 gene. ncRNA _CCND1 associates with and recruits TLS, an RNA binding protein, to the cyclin D1 promoter. The ncRNA _CCND1–TLS complex inhibits the CBP/p300–pCAF–CREB coactivator complex and thereby prevents cyclin D1 gene transcription. b DNA damage induces the expression of the lncRNA, gadd7, which dissociates TDP-43 from the CDK6 mRNA to destabilize it, and CDK6 is thereby downregulated, inhibiting the G1/S transition. The lncRNAs gadd7 and ncRNA _CCND1 may collaboratively participate in the G1 checkpoint in response to DNA damage

Fig. 3

Model showing the proposed mechanisms of ANRIL-mediated regulation of the INK4 locus. a Model of ANRIL-mediated repression of the INK4 locus. ANRIL binds to the PRC2 complex to recruit it to the INK4 locus. Then, histone H3K27 methylation (M) is mediated by EZH2 in the PRC2 complex with ANRIL, which is recognized by CBX7 to recruit the PRC1 complex to the region. Histone H2AK119 monoubiquitination (Ub) is thereby induced to repress the transcription of INK4. b Excess RAS signaling suppresses the expression of ANRIL. Overexpression of activated H-RasG12V in WI38 fibroblasts promotes excess RAS signaling and suppresses ANRIL expression. Then, p15 and p16 are induced and the cell cycle undergoes arrest, inducing a premature senescence-like phenotype

Fig. 4

Model showing the proposed mechanisms of lncRNA-mediated regulation of the RB pathway. pRB binds target transcription factors such as E2F and inhibits their activity in the G1 phase. Cyclin Ds-CDK4/6 phosphorylate pRB and activate E2F-mediated transcription in late G1, which regulates the expression of several growth-promoting genes and S phase entry. The transcription of H19 lncRNA from the H19 locus is mediated by E2F1. H19 lncRNA is processed to generate miR-675, which binds to RB mRNA and inhibits its translation

Fig. 5

Model showing the proposed mechanisms of lncRNA-mediated regulation of the p53 pathway. p53 controls cell cycle arrest, repair, and apoptosis in response to DNA damage. lncRNA-RoR binds to hnRNP-I and collaboratively suppresses p53 mRNA translation. This is an autoregulatory feedback loop that controls p53 levels. In response to DNA damage, p53 is stabilized and activated via phosphorylation mediated by the ATM/ATR pathway. p53 directly binds the target genes and regulates their expression to control cell cycle arrest, repair, and apoptosis. eRNAs are involved in promotion of p53-target genes in p53-dependent cell cycle arrest. p21 and lncRNA-p21, which is transcribed near the p21 ^Cip1 gene, are p53-target genes. lncRNA-p21 controls the expression of some p53-target genes. p53 function is partially mediated by gene regulation via lncRNA-p21