Emerging roles of long non-coding RNAs in the p53 network

Figures & data

Table 1. LncRNAs that interface with p53-pathway.

LncRNA	p53-regulated?	Function	Mechanism	Ref.
LNCRNAs regulated by p53:
LincRNA-p21	Induced by p53 (direct)	Pro-apoptotic and positively contribute to p53-activity	Activates p53-transcriptional activity in cis and trans based on interacting proteins. Also regulates genes at post-transcriptional level.	[25,71,72]
DINO	Induced by p53 (indirect)	p53-dependent gene expression, cell cycle arrest and apoptosis in response to DNA damage	Bound to p53 and promoted its stabilization and transcriptional activity	[28]
LINC-PINT	Induced by p53 (direct)	Pro-proliferation and anti-apoptotic in MEFs and anti-proliferative in HCT116 cells	Interacts with Suz12 subunit of PRC2 complex in MEFs to suppress expression of genes involved in cell proliferation	[32]
PANDA	Yes, direct	Anti-apoptotic and maintains survival following DNA damage	Interacts with NF-YA and restricts, NF-YA mediated activation of apoptotic genes. Also interacts with SAFA and by recruiting PRC complexes, represses expression of senescence-promoting genes	[29,30]
PR-lncRNA1, PR-lncRNA10	Induced by p53 (direct)	Negative regulators of cell survival and proliferation	Enhances p53-transcriptional activity by unknown mechanism	[45]
NORAD	Induced by p53 (indirect)	Maintains genomic stability	Sequesters PUMILIO protein PUM2 from repressing the gene targets involved in DNA repair and DNA replication.	[73]
GUARDIN	Induced by p53 (direct)	Maintains genomic integrity	Sequesters miR-23a to sustain TRF2 expression. Stabilizes BRCA1 by acting as RNA-scaffold to stabilize BRCA1-BARD1 interactions.	[37]
NEAT1	Induced by p53 (direct)	Pro-proliferation, oncogenic	Essential component of nuclear paraspeckles, sponge miRNAs, and sequesters chromatin regulatory proteins to regulate gene expression.	[38,41,42]
PVT1	Induced by p53 (direct)	Oncogenic, displays distinct effects in the p53 pathway depending on the cellular context	Multiple mechanisms, including acting as competitive endogenous RNA for miRNAs, and interacts with MYC protein to prevent its degradation.	[44,74]
TUG1	Induced by p53 (direct)	Cellular context-specific role in regulating cell proliferation	Recruits PRC2 complex to repress target gene expression	[46,75]
Linc-ROR	Induced by p53 (direct)	Depletion results in activation of p53 response and promote survival of ESCs and iPSCs	Binds to hnRNP I and inhibits the translation of p53 in response to DNA damage	[58,59]
LINP1	Repressed by p53 (indirect)	Overexpressed in triple-negative breast cancer, depletion delays IR-induced DNA damage	unknown	[76]
PINCR	Induced by p53 (direct)	Promotes p53 activity at subset of p53 targets	Binds to Metrin3 and recruits p53 to enhancer regions	[47]
TRMP	Induced by p53 (direct)	Pro-survival	Suppresses internal ribosomal entry site (IRES)-dependent translation of p27.	[77]
DDSR1	Induced by p53 (indirect)	Pro-survival, negatively regulates p53-activity	Recruits homologous recombination repair factors, BRCA1 and RAP80 to the double strand breaks	[78]
H19	Repressed by p53 (direct)	Associated with several cancers, partial inactivation of p53 activity	Binds to p53 and suppresses its activity	[64,79]
LNCPRESS1	Repressed by p53 (direct)	Pluripotency associated, maintains stemness of hESCs	Molecular decoy to keep SIRT6 away from chromatin to maintain H3K56ac and activation of pluripotency genes	[23]
LED	Induced by p53 (direct)	Suppresses cell proliferation, promotes the transcription of some p53-eRNAs	Associates with enhancer domains in chromatin and regulates production of eRNAs, regulates p53 binding at enhancers	[24]
Linc-475	Induced by p53 (direct)	Induces p53-dependent cell cycle inhibitory response	Required for proper p53 and RNA polymerase II binding at p21 promoter	[48]
PURPL	Induced by p53 (direct)	Pro-proliferation, suppresses basal p53 levels	Partially by preventing p53-MYBBP1A complex formation	[80]
HOTAIR	Repressed by p53 (direct)	Oncogenic lncRNA	Recruits PRC2 and LSD1/CoREST/REST complexes to repress target gene expression	[13,49]
LncRNAs that regulate p53 activity:
MALAT1	No	Pro-proliferation, depletion results in activation of p53 and its targets	Regulates gene expression and pre-mRNA splicing by interacting with splicing factors. Reduces p53 activity by regulating p53 at both transcriptional and post-transcriptional levels.	[54,56,57,81,82]
MEG3	No	Overexpression induces p53 protein levels and transcriptional activity	Downregulates MDM2 expression	[50,83,84]
PSTAR	No	Inhibits cell proliferation and tumorigenicity through inducing p53-mediated cell cycle arrest	Binds to hnRNP K, enhances its sumoylation, promote hnRNP K interactions with p53 and block MDM2 mediated p53 ubiquitination	[66]
MT1JP	No	Regulates G1/S checkpoint to control cell proliferation	Binds to TIAR and regulates translation of TP53 mRNA and thus p53 protein	[85]
LOC572558	No	Overexpression inhibits proliferation and induces apoptosis	Mechanism is unclear but correlates with reduced phosphorylation of Akt, MDM2 and increased phosphorylation of p53	[86]

Figure 1. P53-regulated lncRNAs control diverse biological processes. Active p53 in response to DNA damage or other stimuli transcriptionally regulates the expression of several lncRNAs. LincRNA-p21 interacts with hnRNP K to promote gene repression and p53-mediated apoptosis. DINO stabilizes p53 protein in order to mediate and amplify p53-response. PR-lncRNA1 and PR-lncRNA-10 inhibit cell survival and promote apoptosis. NEAT1 forms nuclear paraspeckles and regulate gene expression to achieve context-specific tumour suppression or proliferation. PANDA exert pro-survival functions by sequestering transcription factor NF-YA away from the promoter of pro-apoptotic genes and recruits SAFA/PRC2 complex on senescence-promoting genes. TUG1 can promote or inhibit cell proliferation depending on cellular context or tumour type. Human and murine orthologues of PINT have distinct functions. LED and PINCR promote p53 activity at a subset of p53 targets by enhancing recruitment of p53 at specific enhancers. LNCPRESS1 is a pluripotency-specific p53-repressed lncRNA that sequesters histone deacetylase, SIRT6 away from promoters of pluripotency genes in order to maintain stemness. NORAD maintains genomic stability by sequestering PUMILIO proteins. GUARDIN stabilizes BRCA1 and increase expression of TRF2 to maintain genomic stability.

Figure 2. LncRNAs regulate p53 activity. Several lncRNAs, some themselves regulated by p53 modulate the p53-response by multiple mechanisms including, destabilizing p53-interactions with its negative regulator MDM2 (MEG3, PSTAR), increasing p53 levels by increased translation (MT1JP), phosphorylation of p53 (LOC572558) or direct interactions with p53 to stabilize the protein (DINO), and downregulate p53 levels via miRNAs or reduced the transcript stability (LincRNA-ROR, H19) or downregulating p53 acetylation and stabilization (MALAT1).

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