HP1BP3

Contents:

1. HP1BP3
2. Interpro results
3. Essential roles in viability and growth
4. HP1BP3 in hypoxia-induced oncogenesis
5.  Novel Regulator of Cell Cycle Progression

 

1. HP1BP3

Component of heterochromatin that maintains heterochromatin integrity during G1/S progression and regulates the duration of G1 phase to critically influence cell proliferative capacity. Mediates chromatin condensation during hypoxia, leading to increased tumor cell viability, radio-resistance, chemo-resistance and self-renewal.  HP1BP3 is a key mediator of tumor progression and cancer cell acquisition of therapy-resistant traits, and thus might represent a novel therapeutic target in a range of human malignancies.

 

https://www.ebi.ac.uk/interpro/sequencesearch/iprscan5-S20170103-085925-0362-78920355-pg

 

1. Interpro results

Domains and repeat in first 160 amino acids:

   Armadillo-type fold: This entry represents a structural domain with an armadillo (ARM)-like fold, consisting of a multi-helical fold comprised of two curved layers of alpha helices arranged in a regular right-handed superhelix, where the repeats that make up this structure are arranged about a common axis. These superhelical structures present an extensive solvent-accessible surface that is well suited to binding large substrates such as proteins and nucleic acids.

http://www.ebi.ac.uk/interpro/entry/IPR016024ex

 

 W2 Domain:  The W2 domain (two invariant tryptophans) is a region of ~165 amino acids which is found in the C terminus of the following eIFs [PMID: 8520487, PMID: 10958635, PMID: 14681227, PMID: 16616930, PMID: 16781736]:

• Eukaryotic translation initiation factor 2B epsilon (eIF-2B-epsilon).
• Eukaryotic translation initiation factor 4 gamma (eIF-4-gamma).
• Eukaryotic translation initiation factor 5 (eIF-5), a GTPase-activating protein (GAP) specific for eIF2.

http://www.ebi.ac.uk/interpro/entry/IPR003307

 

 MIF4G-like domain:  The MIF4G domain is a structural motif with an ARM (Armadillo) repeat-type fold, consisting of a 2-layer alpha/alpha right-handed superhelix. Family members contain two or more structurally similar domains of this fold connected by unstructured linkers; this entry covers types 1, 2 and 3 MIF4G-like domains. MIF4G domains are found in several proteins involved in RNA metabolism, including eIF4G (eukaryotic initiation factor 4-gamma), eIF-2b (translation initiation factor), UPF2 (regulator of nonsense transcripts 2), and nuclear cap-binding proteins (CBP80, CBC1, NCBP1), although the sequence identity between them may be low.

In eIF4G, the MIF4G domain binds eIF4A, eIF3, RNA and DNA.

The activity of eIF4G in translation initiation could be regulated through intra- and inter-protein interactions involving the ARM repeats

                      http://www.ebi.ac.uk/interpro/entry/IPR016021

 

 

 

https://en.wikipedia.org/wiki/HP1BP3

 

 HP1BP3 deficiency in mice results in severe dwarfism and impaired bone mass, caused by altered endocrine IGF-1 signaling. The gene is highly expressed in the brain and a number of behavioral phenotypes have been described for the mice. Lack of HP1BP3 led to impaired maternal behavior and reduced anxiety, leading to a dramatic reduction in litter survival. This may be related to the connection between HP1BP3 and postpartum depression in humans. Finally, HP1BP3 has been implicated in Alzheimer's disease.

 Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty three tests were carried out and six significant phenotypes were reported. Fewer homozygous mutant embryos were identified during gestation than predicted by Mendelian ratio. Homozygous mutant female adults had decreased body weight, heart weight and bone mineral density, and increased blood urea levels and T cell number.

 

3)HP1BP3 is a novel histone H1 related protein with essential roles in viability and growth

1. Benjamin P. Garfinkel¹,^*, 
2. Naomi Melamed-Book², 
3. Eli Anuka¹, 
4. Michael Bustin³ and
5. Joseph Orly¹,^*

 

http://nar.oxfordjournals.org/content/early/2015/02/07/nar.gkv089.full

Significantly, Hp1bp3^−/− mice present a dramatic phenotype with 60% of pups dying within 24 h of birth and the surviving animals exhibiting a lifelong 20% growth retardation. We suggest that HP1BP3 is a ubiquitous histone H1 like nuclear protein with distinct and non-redundant functions necessary for survival and growth.

 

 Binding of HP1BP3 to chromatin depends on both its C and N terminal regions and is affected by the cell cycle and post translational modifications.

 We find that HP1BP3 is a novel histone H1 related protein endowed with unique chromatin binding determinants and involved in the modulation of gene expression.  

Proper cooperative binding of H1 to nucleosomes has been shown to induce chromatin compaction and a recent study found that HP1BP3 can compact chromatin in vivo.

 Deletion of the NTD of HP1BP3 also decreased the affinity of the protein for chromatin. Interestingly, this deletion had the added effect of redistributing the protein within the nucleus, with very high enrichment in the nucleoli.

 

 Cell cycle–related chromatin decondensation and phosphorylation of H1 have been shown to be associated with changes in the intranuclear mobility of the protein, and inhibition of H1 kinases decreases H1 mobility in living cells. FRAP experiments have also demonstrated that exposure of cells to histone deacetylase inhibitors reduces the binding of H1 to chromatin. We find that HP1BP3 follows these same patterns, showing increased mobility with progression of the cell cycle and following treatment with TSA and decreased mobility in response to kinase inhibition.

 

 

 

4)Quantitative profiling of chromatome dynamics reveals a novel role for HP1BP3 in hypoxia-induced oncogenesis.

Dutta B¹, Yan R¹, Lim SK², Tam JP¹, Sze SK³.

http://www.mcponline.org/content/13/12/3236.long

 

 Hypoxia-inducible factors mediate DNA methylation, histone modification, and host cell expression of regulatory RNAs and chromatin-modeling factors that modulate gene expression in response to low-oxygen conditions. However, hypoxia can also induce histone modification and chromatin remodeling via hypoxia-inducible factor–independent pathways, indicating that additional mechanisms of epigenetic regulation can shape the cellular response to restricted oxygen supply, and potentially increase cell survival and promote angiogenesis in hypoxic conditions 

Hypoxia-induced changes in the composition of the chromatin-associated proteome (chromatome) are therefore likely to alter gene expression and promote clonal evolution in developing tumors. Although better knowledge of chromatome dynamics in low-oxygen conditions is likely to increase our understanding of the molecular events that drive tumor progression, few quantitative proteomic studies of chromatome modulation by hypoxia have been conducted to date.

HP1BP3 depletion inhibits cancer cell renewal during hypoxia/re-oxygenation.

We treated HP1BP3-depleted A431 cells (or mock-depleted control cells) with either 10 Gy ionizing radiation or doxorubicin for 24 h and assessed cell viability via MTT assay. We observed that HP1BP3 depletion increased cancer cell susceptibility to both radiation treatment and doxorubicin exposure.     Taken together, our data reveal a novel role for HP1BP3-induced heterochromatinization in genetic reprogramming of cancer cells during hypoxia, leading to the acquisition of radio- and chemoresistant characteristics.

 

Chromatin-binding protein HP1BP3 altered its binding topology in a hypoxia-dependent manner and promoted heterochromatinization in order to modulate gene expression and induce cancer cells to acquire a CSC-like phenotype. Accordingly, depletion of HP1BP3 decreased cancer cell viability, therapy resistance, and stemness under hypoxic conditions, leading to decreased tumorigenic potential of these cells both in vitro and in vivo. 

5)Profiling of the Chromatin-associated Proteome Identifies HP1BP3 as a Novel Regulator of Cell Cycle Progression

Bamaprasad Dutta,^‡ Yan Ren,^‡ Piliang Hao,^‡ Kae Hwan Sim,^‡ Esther Cheow,^‡ Sunil Adav,^‡ James P. Tam,^‡ and Siu Kwan Sze^‡§

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159643/

 

 HP1BP3 protein maintains heterochromatin integrity during G_1–S progression and regulates the duration of G₁ phase to critically influence cell proliferative capacity.

Our Western blot analysis further revealed that the chromatin association level of HP1BP3 was increased during both early G₁ phase and G₁/S transit relative to G₂/M phase, consistent with a putative role for this protein in chromatin organization. The proteomic data therefore suggested that “cluster b1′” proteins are likely to regulate gene transcription by maintaining heterochromatin integrity during G₁–S progression.

HP1BP3 regulates chromatin structure in G₁ phase by inter-converting euchromatin and heterochromatin to activate or silence specific genes.

 These experimental data indicated that HP1BP3 may be required for chromatin packing into heterochromatin, and that depletion of HP1BP3 disrupts heterochromatin structure caused by unfolding of chromatin.

 We identified a total of 384 proteins that were differentially expressed in HP1BP3-depleted cells (iTRAQ ratio >1.2 or <0.8), comprising 176 up-regulated and 208 down-regulated proteins. The identified proteins were then classified according to their subcellular localization and assigned biological functions . Our quantitative proteomic data suggested that depletion of HP1BP3 altered the protein expression levels in the resulting phenotype. Altered protein expression because of HP1BP3 depletion suggested that HP1BP3 not only involve in the maintenance of heterochromatin integrity but also involve in transcription regulation.

 

HP1BP3 depletion accelerated G₁/S transit and enhanced cell proliferation via the putative mechanism of activating previously silenced genes in regions of heterochromatin. Taken together, we propose that HP1BP3 regulates gene transcription by maintaining heterochromatin integrity and thus regulates the length of G₁ phase to maintain cell cycle progression.

 

 

During the hypoxia condition normal cell viability decreases and cell cycle-arrest at G0-G1 phase. However, at that condition HP1BP3 promotes heterochromatinization and induces transcriptional reprogramming, thereby promote cell survival. Also reduces apoptosis.  In shark in N-terminal additiononal 160 amino acid long peptide gained. According their sequences, they are ARM repeat, W2 domains and  MIF4G-like domains. These domains usually found in eukaryotic translation initiation factors, which help to recognize and bind large substrates like proteins and nucleotides. So, it is very interesting that whale shark has W2 domain gain in HP1BP3 protein. That domain helps to improve HP1BP3 binding property and gives advantages in protein function.