Detailed entry information

Protein Information (annotations from UniProt)

Database IDHIV0002135
UniProt IDO15055
Primary gene name(s)PER2
Synonym gene name(s)KIAA0347
Protein namePeriod circadian protein homolog 2
Protein functionTranscriptional repressor which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa', about and 'diem', day and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus, SCN of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers, German for 'timegivers'. The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components, CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CRY2 plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications, PTMs are important for determining the period, tau of the rhythms, tau refers to the period of a rhythm and is the length, in time, of one complete cycle. A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndrome and aging. A transcription/translation feedback loop, TTFL forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes, involved in key metabolic processes, harboring E-box elements, 5'-CACGTG-3' within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress ARNTL/BMAL1 transcription, respectively. PER1 and PER2 proteins transport CRY1 and CRY2 into the nucleus with appropriate circadian timing, but also contribute directly to repression of clock-controlled target genes through interaction with several classes of RNA-binding proteins, helicases and others transcriptional repressors. PER appears to regulate circadian control of transcription by at least three different modes. First, interacts directly with the CLOCK-ARTNL/BMAL1 at the tail end of the nascent transcript peak to recruit complexes containing the SIN3-HDAC that remodel chromatin to repress transcription. Second, brings H3K9 methyltransferases such as SUV39H1 and SUV39H2 to the E-box elements of the circadian target genes, like PER2 itself or PER1. The recruitment of each repressive modifier to the DNA seems to be very precisely temporally orchestrated by the large PER complex, the deacetylases acting before than the methyltransferases. Additionally, large PER complexes are also recruited to the target genes 3' termination site through interactions with RNA-binding proteins and helicases that may play a role in transcription termination to regulate transcription independently of CLOCK-ARTNL/BMAL1 interactions. Recruitment of large PER complexes to the elongating polymerase at PER and CRY termination sites inhibited SETX action, impeding RNA polymerase II release and thereby repressing transcriptional reinitiation. May propagate clock information to metabolic pathways via the interaction with nuclear receptors. Coactivator of PPARA and corepressor of NR1D1, binds rhythmically at the promoter of nuclear receptors target genes like ARNTL or G6PC. Directly and specifically represses PPARG proadipogenic activity by blocking PPARG recruitment to target promoters and thereby inhibiting transcriptional activation. Required for fatty acid and lipid metabolism, is involved as well in the regulation of circulating insulin levels. Plays an important role in the maintenance of cardiovascular functions through the regulation of NO and vasodilatatory prostaglandins production in aortas. Controls circadian glutamate uptake in synaptic vesicles through the regulation of VGLUT1 expression. May also be involved in the regulation of inflammatory processes. Represses the CLOCK-ARNTL/BMAL1 induced transcription of BHLHE40/DEC1 and ATF4. Negatively regulates the formation of the TIMELESS-CRY1 complex by competing with TIMELESS for binding to CRY1. {ECO:0000250|UniProtKB:O54943}.
Subcellular locationIsoform 1: Nucleus. Cytoplasm {ECO:0000250|UniProtKB:O54943}. Cytoplasm, perinuclear region {ECO:0000250}. Note=Nucleocytoplasmic shuttling is effected by interaction with other circadian core oscillator proteins and/or by phosphorylation. Translocate to the nucleus after phosphorylation by CSNK1D or CSNK1E. Also translocated to the nucleus by CRY1 or CRY2. PML regulates its nuclear localization.;
SUBCELLULAR LOCATION: Isoform 2: Nucleus, nucleolus {ECO:0000269|PubMed:24202686}.
ECO codeClick here for more information.
Amino acid sequence
FASTA format: O15055
Gene Ontology
(Biological Process)
Complete annatation
circadian regulation of gene expression [GO:0032922];
circadian regulation of translation [GO:0097167];
circadian rhythm [GO:0007623];
fatty acid metabolic process [GO:0006631];
gluconeogenesis [GO:0006094];
glycogen biosynthetic process [GO:0005978];
histone H3 deacetylation [GO:0070932];
lactate biosynthetic process [GO:0019249];
negative regulation of circadian rhythm [GO:0042754];
negative regulation of fat cell proliferation [GO:0070345];
negative regulation of protein ubiquitination [GO:0031397];
negative regulation of transcription, DNA-templated [GO:0045892];
negative regulation of transcription from RNA polymerase II promoter [GO:0000122];
negative regulation of transcription regulatory region DNA binding [GO:2000678];
regulation of cell cycle [GO:0051726];
regulation of circadian rhythm [GO:0042752];
regulation of glutamate uptake involved in transmission of nerve impulse [GO:0051946];
regulation of insulin secretion [GO:0050796];
regulation of neurogenesis [GO:0050767];
regulation of vasoconstriction [GO:0019229];
response to ischemia [GO:0002931];
transcription, DNA-templated [GO:0006351];
white fat cell differentiation [GO:0050872]
Gene Ontology
(Molecular Function)
Complete annatation
transcription coactivator activity [GO:0003713];
transcription factor activity, transcription factor binding [GO:0000989];
transcription regulatory region sequence-specific DNA binding [GO:0000976];
ubiquitin binding [GO:0043130]
Gene Ontology
(Cellular Component)
Complete annatation
cytoplasm [GO:0005737];
nucleolus [GO:0005730];
nucleoplasm [GO:0005654];
nucleus [GO:0005634];
perinuclear region of cytoplasm [GO:0048471]
Protein-protein interaction114387
Phylogenetic treeO15055
HIV replication factor status Zhou et al., Cell. Host. Microbe., 2008
Brass et al., Science, 2008
Smith et al., J. Immunol, 2010
gene status
Lu et al., J. Virol., 2011
      Folds changes 8h: unknown; Folds changes 16h: unknown; Tested: unknown;
Schoggins JW and Rice CM, Curr. Opin. Virol., 2011
      Targeted viruses: unknown
      Viral life cycle: unknown
      Mechanism related to antiviral activity: unknown
Anti-viral restriction factor Liu et al., Retrovirology, 2011
      unknown (Triplicates)

Gene Expression Profile       top

            Up-regulated;            Down-regulated

For brief introduction to each study, please go to the help page.

Gene expression during HIV latency

(1). Mohammadi et al., PLoS Pathog., 2014

Differentially expressed transcripts (Pairwise) during latency and subsequent viral reactivation using several agents - Primary CD4+ T-cell based model

DMSO: Dimethyl suloxyde (negative control) - 0.0033% final
SAHA: Vorinostat (Histone deacetylase inhibitor) - 0.5 μM
CD3: TCR Stimulation by IL-2+ antiCD3/anti-CD28 antibodies
IL7: Interleukin-7 based stimulation
DISU: Disulfiram (alcohol dehydrogenase inhibitor) - 0.5 μM
AZA: 5-azacytidine (AZA; DNA methylation inhibitor) - 1 μM
Experimental Condition Log2 Fold Change P value Adjusted P value
AZA vs. CD30.8993372141722640.006749561446053540.0186933829685628
AZA vs. DISU-0.2089075590000760.4175326555339960.911342924190573
AZA vs. IL70.3020448917763790.125991984395570.892098508590985
AZA vs. SAHA-0.4296302442317350.08648708668631590.367779447172759
DISU vs. CD3-1.11940696679450.002484334350074560.00902419229891667
DISU vs. IL70.5012847285597120.05065206716453860.297228459519432
DISU vs. SAHA-0.2189443899293090.4590613746987570.798443621244659
DMSO vs. AZA0.04986215934279970.7746750802599421
DMSO vs. CD3-0.8573520148561990.008191327943086410.0210046562489527
DMSO vs. DISU0.2579672453705050.2985778723868910.807887568985919
DMSO vs. IL70.2595409081852460.1600099762133650.666357645233941
DMSO vs. SAHA-0.4857562476995530.0443396692924890.235296885882782
HIV vs. Mock in Activation0.2760990092518250.6582962436870370.999983755607037
HIV vs. Mock in Latency0.006701601688957990.9804752235279390.999834320637052
IL7 vs. CD3-0.5923250488541250.0674578104925370.139474475668779
SAHA vs. CD3-1.352449029614260.0002036215023223380.000896458089394574
SAHA vs. IL7-0.7337459583011340.003346482819889030.0288886447909927
(2). Iglesias-Ussel et al., J. Virol., 2013

Up and Downregulated transcripts during Latency (Latently infected CD4+ T cells vs Uninfected)- Primary CD4+Tcell based model
Log2 Fold Change P Value
unknown unknown

Gene expression during HIV infection and replication

(1). Imbeault et al., PloS Pathog., 2012

Transcriptomic profiling of HIV-1 infected CD4+ T cells - Primary CD4+ T cells
Experiment type Log2 Fold Change P Value Adjusted P Value
Infected vs. Mock unknown unknown unknown
Infected vs. Bystander unknown unknown unknown
(2). Lefebvre et al., J. Virol., 2011

Transcriptome analysis of T-cell line (Sup T1)
Log2 Fold Change unknown
(3). Li et al., J. Immunol., 2013

Lymphatic tissue
Acute Fold Change Acute P Value Asymt Fold Change Asypt P Value AIDS Fold Change AIDS P Value
unknown unknown unknown unknown unknown unknown
(4). Chang et al., MBio., 2011

Transcriptome analysis of T-cell line (Sup T1)

Derived from Sherrill-Mix et al., BMC Retrovirol., 2015 cross validation
Up-regulated (True) FALSE
(5). Sherrill-Mix et al., BMC Retrovirol., 2015

Deep RNA-seq analysis of primary human T cell infected with low passage HIV isolate HIV89.6 - Primary CD4+ T cell based
Test Status Log2 Fold Change P Value
OK 0.22746 0.141614
(6). Rotger et al., PLoS Pathog., 2010

Genome-wide mRNA expression of CD4+ T cells from HIV-infected patient
(Genes differentially expressed (at adjusted p<0.01) according to the empirical Bayes approach)
Log2 Fold Change P Value
unknown unknown

Proteomic/Transcriptomics studies indicating differentially expressed genes mediated by HIV

(1). Greenwood et al., Elife, 2016

Activated (CD3/CD28) Primary human CD4+ T cells infected with pNL4-3-dE-EGFP. The table shows the complete (unfiltered) TMT (tandem mass tag)-based proteomic time course dataset
6 h 24 h 48 h 72 h RTi
unknown unknown unknown unknown unknown
(2). Navare et al., Virology, 2012

SUP-T1 cell line
FC-4hpi P-value FC-8hpi P-value FC-20hpi P-value Category
unknown unknown unknown unknown unknown unknown unknown
(3). Hyrcza et al., J. Virolo., 2007

Primary human CD4+ and CD8+ T Cells
Affymetrix Prob ID Fold Change In CD8? Category
unknown unknown unknown unknown

Protein Overview       top

Drug-protein Interaction       (annotations from DrugBank)      top

not found

Protein Secondary Structure       (annotations from PDB)      top

not found

HIV-1 Interaction       (annotations from NCBI HIV-1 Interaction Database)      top

not found

Metabolic/Signalling Pathway       (annotations from KEGG database)      top

Pathway Accession Number Description
hsa04710 Circadian rhythm - Homo sapiens (human)
hsa04713 Circadian entrainment - Homo sapiens (human)
hsa05168 Herpes simplex infection - Homo sapiens (human)
hsa05202 Transcriptional misregulation in cancer - Homo sapiens (human)