Reptin

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Reptin is a tumor repressor protein that is a member of the ATPases Associated with various cellular Activities (AAA+) helicase family and regulates KAI1. [1] Desumoylation of reptin alters the repressive function of reptin and its association with HDAC1. The sumoylation status of reptin modulates the invasive activity of cancer cells with metastatic potential. Reptin was reported in 2010 to be a good marker for metastasis. Another name for reptin, RuvB-like 2 (RUVBL2 or RVL2) comes from its similarity to RuvB, an ATP-dependent helicase found in bacteria. [2] Reptin is highly conserved, being found in yeast, drosophila, and humans. It presents itself as a member of a number of different protein complexes, most of which function in chromatin modification, including PRC1, TIP60/NuA4 and INO80. Hence, it also has the names INO80J, TIP48, and TIP49B. [3] [4] In the majority of its functions, reptin is paired with a very similar protein, pontin (RUVBL1). [2]

Contents

Structure

Human reptin is composed of 463 amino acids. [5] It has ATPase regions, a DNA binding region, and regions for binding to other reptin proteins to form a hexamer ring as well as pontin and other proteins. The reptin hexamer is bound to a pontin hexamer in most, but not all of the complexes that contain reptin. The DNA binding regions are in the hole at the center of the hexamer rings, where, as with other helicases, the DNA can be fed through to separate the strands by using energy stored in the ATP bound to ATPase domains of the helicase proteins. [6] It is not known if reptin hexamers have a wide enough opening to accommodate double stranded DNA; however, reptin-pontin dodecamers are large enough for double stranded DNA to pass through, while pontin hexamers are only large enough to accommodate single stranded DNA. [7]

Functions

Reptin is involved in a very wide range of cell processes, which can vary from species to species.

Reptin coordinates with a number of proteins that are involved in cancer and cancer suppression. These include Telomerase, P53, and HINT1. [2] Telomerase is a protein complex with telomerase reverse transcriptase (TERT), an RNA component (TERC), dyskerin, which binds TERC, reptin, pontin, and a number of other proteins, and both reptin and pontin have been shown to be key factors in telomerase assembly and activity. Telomerase is an important factor in cancer because it allows cancer cells to divide indefinitely without cutting into and destroying their genomes, so reptin promotes cancer in this case. [8]

The inhibition of p53 by reptin occurs by the binding of reptin and AGR2 to the p53 tetramer-forming domain. About half of all human cancer types have p53 inactivated, as p53 functions to prevent cancer and kill cancer cells in a number of ways. [9] [10] Hint1 is a tumor suppressing protein that counteracts cancer by inhibiting TCF-β-catenin complex function. This complex enhances transcription of specific genes, including Wnt1 and the metastasis-associated protein KAI1, and thereby causes cancer growth. This is accomplished when Hint1 binds to reptin, which breaks up the β-catenin complex, suppressing transcription. [11] This complex differs from complexes such as INO80 and NuA4 in that reptin acts against the function of pontin, which promotes transcriptional activity by β-catenin. [2]

DNA repair

Reptin is a component of both the INO80 and the TIP60/NuA4 protein complexes, which function in repairing DNA double-stranded breaks. Such breaks may lead to cancer and other issues. Researchers have found that reptin is highly important in several functions of both of these complexes. [12] The INO80 complex has been shown to directly participate in both the homologous recombination and the non-homologous end joining processes for fixing double stranded breaks. In addition, it removes histones from the broken DNA to allow repair systems access. Human INO80 also activates genes that resume replication fork action when the replication fork stops at a double stranded break, and it is likely involved in the process directly as well. It has been shown that, in the absence of INO80, there are significantly more double stranded breaks during replication. [3]

Reptin is a component of the NuA4 protein complex, which recruits and assists DNA double stranded break repair systems via the acetylation of histones H4 and H2A. Both reptin and pontin are essential for the acetylation function and the structural formation of the NuA4 complex. [12] The repair stimulated by NuA4 is by homologous recombination. [13]

Developmental regulation

Improper expression of developmental genes such as Wnt may contribute to cancer; however, expression of developmental genes is also vital to proper development. The involvement of reptin in regulating the Wnt pathway makes it important to the many processes that Wnt guides. Through its role as part of chromatin modification complexes, reptin helps regulate gene expression by altering the packing of DNA, which can block transcription, realign transcription factors to activate or inhibit gene expression, and perform various other regulatory tasks. Reptin's role in the β-catenin complex is highly important to the regulation of transcription. [11]

Reptin also is a component of the polycomb repressive complex 1 (PRC1), where it assists regulation of polycomb group proteins (PcG). In turn, PcG proteins regulate chromatin structure to turn Hox genes on and off, thereby regulating the development of an organism. Reptin can have varying effects on PcG repression. For example, in drosophila, reptin mutations affected multiple sex comb genes with varying intensity, but for certain PRC1-associated sex comb genes reptin mutations had no connection to their expression. [14] Generally, reptin and pontin have opposite effects on Hox and PcG gene expression. [11]

Miscellaneous functions

In addition to those functions listed above, reptin is also used in a surprising range and number of other cellular activities. In Chlamydomonas reinhardtii , reptin was shown to be an indirect key factor in inducing flagellar repair. [15] In addition, reptin directly participates in zebrafish kidney cilia motility by binding to LrrC6 in the complex for forming dynein arms in the cilia. [16] Reptin also plays a part in the synthesis of small nucleolar ribonucleoproteins (snoRNP) which process non-messenger RNAs. [17]

Reptin participates in apoptosis signaling by binding to the ATPase p400 (SWI2/domino) which interacts with an apoptosis signal cascade. This event occurs in the NuA4 protein complex. [12]

One more function of reptin is its interaction with heat shock protein 90 (HSP90), where it forms the complex, R2TP. This complex functions mainly in processing snoRNA and assembling RNA polymerase II (RNAP II). [17]

Related Research Articles

Transcription (biology) Process of copying a segment of DNA into RNA

Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules called non-coding RNAs (ncRNAs). Averaged over multiple cell types in a given tissue, the quantity of mRNA is more than 10 times the quantity of ncRNA. The general preponderance of mRNA in cells is valid even though less than 2% of the human genome can be transcribed into mRNA, while at least 80% of mammalian genomic DNA can be actively transcribed, with the majority of this 80% considered to be ncRNA.

Histone acetyltransferase Enzymes that catalyze acyl group transfer from acetyl-CoA to histones

Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-N-acetyllysine. DNA is wrapped around histones, and, by transferring an acetyl group to the histones, genes can be turned on and off. In general, histone acetylation increases gene expression.

Origin of replication Sequence in a genome

The origin of replication is a particular sequence in a genome at which replication is initiated. Propagation of the genetic material between generations requires timely and accurate duplication of DNA by semiconservative replication prior to cell division to ensure each daughter cell receives the full complement of chromosomes. This can either involve the replication of DNA in living organisms such as prokaryotes and eukaryotes, or that of DNA or RNA in viruses, such as double-stranded RNA viruses. Synthesis of daughter strands starts at discrete sites, termed replication origins, and proceeds in a bidirectional manner until all genomic DNA is replicated. Despite the fundamental nature of these events, organisms have evolved surprisingly divergent strategies that control replication onset. Although the specific replication origin organization structure and recognition varies from species to species, some common characteristics are shared.

RSC is a member of the ATP-dependent chromatin remodeler family. The activity of the RSC complex allows for chromatin to be remodeled by altering the structure of the nucleosome.

Beta-catenin

Catenin beta-1, also known as β-catenin, is a protein that in humans is encoded by the CTNNB1 gene.

In molecular biology, origin recognition complex (ORC) is a multi-subunit DNA binding complex that binds in all eukaryotes and archaea in an ATP-dependent manner to origins of replication. The subunits of this complex are encoded by the ORC1, ORC2, ORC3, ORC4, ORC5 and ORC6 genes. ORC is a central component for eukaryotic DNA replication, and remains bound to chromatin at replication origins throughout the cell cycle.

Eukaryotic DNA replication

Eukaryotic DNA replication is a conserved mechanism that restricts DNA replication to once per cell cycle. Eukaryotic DNA replication of chromosomal DNA is central for the duplication of a cell and is necessary for the maintenance of the eukaryotic genome.

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

RUVBL2

RuvB-like 2 , also known as RUVBL2, is a human gene coding for a protein belonging to the AAA+ family of proteins.

RuvB-like 1

RuvB-like 1 , also known as RUVBL1 and TIP49, is a human gene. RUVBL1 can form a hexamer. The hexamer can form a dodecamer with RUVBL2 protein. Possesses single-stranded DNA-stimulated ATPase and ATP-dependent DNA helicase activity; hexamerization is thought to be critical for ATP hydrolysis and adjacent subunits in the ring-like structure contribute to the ATPase activity.

ERCC6

DNA excision repair protein ERCC-6 is a protein that in humans is encoded by the ERCC6 gene. The ERCC6 gene is located on the long arm of chromosome 10 at position 11.23.

HLTF

Helicase-like transcription factor is an enzyme that in humans is encoded by the HLTF gene.

CHD1 Chromatin remodeling protein that is widely conserved across many eukaryotic organisms

The Chromodomain-Helicase DNA-binding 1 is a protein that, in humans, is encoded by the CHD1 gene. CHD1 is a chromatin remodeling protein that is widely conserved across many eukaryotic organisms, from yeast to humans. CHD1 is named for three of its protein domains: two tandem chromodomains, its ATPase catalytic domain, and its DNA-binding domain.

CHD8

Chromodomain-helicase-DNA-binding protein 8 is an enzyme that in humans is encoded by the CHD8 gene.

The TCF/LEF family is a group of genes that encode transcription factors which bind to DNA through a SOX-like high mobility group domain. They are involved in the Wnt signaling pathway, particularly during embryonic and stem-cell development, but also had been found to play a role in cancer and diabetes. TCF/LEF factors recruit the coactivator beta-catenin to enhancer elements of genes they target. They can also recruit members of the Groucho family of corepressors.

Telomere-binding proteins function to bind telomeric DNA in various species. In particular, telomere-binding protein refers to TTAGGG repeat binding factor-1 (TERF1) and TTAGGG repeat binding factor-2 (TERF2). Telomere sequences in humans are composed of TTAGGG sequences which provide protection and replication of chromosome ends to prevent degradation. Telomere-binding proteins can generate a T-loop to protect chromosome ends. TRFs are double-stranded proteins which are known to induce bending, looping, and pairing of DNA which aids in the formation of T-loops. They directly bind to TTAGGG repeat sequence in the DNA. There are also subtelomeric regions present for regulation. However, in humans, there are six subunits forming a complex known as shelterin.

Shelterin is a protein complex known to protect telomeres in many eukaryotes from DNA repair mechanisms, as well as to regulate telomerase activity. In mammals and other vertebrates, telomeric DNA consists of repeating double-stranded 5'-TTAGGG-3' (G-strand) sequences along with the 3'-AATCCC-5' (C-strand) complement, ending with a 50-400 nucleotide 3' (G-strand) overhang. Much of the final double-stranded portion of the telomere forms a T-loop (Telomere-loop) that is invaded by the 3' (G-strand) overhang to form a small D-loop (Displacement-loop).

HMBOX1

Homeobox containing 1, also known as homeobox telomere-binding protein 1 (HOT1), is a protein that in humans is encoded by the HMBOX1 gene. HMBOX1 directly binds to the double-stranded repeat sequence of telomeres.

The NuA4 histone acetyltransferase complex is a protein complex that has histone acetylase activity on chromatin, as well as ATPase, DNA helicase and structural DNA binding activities. The complex is thought to be involved in double-strand DNA break repair. Subunits of the human complex include HTATIP/TIP60, TRRAP, RUVBL1, RUVBL2, beta-actin and BAF53/ACTL6A. In yeast, the complex has 13 subunits, including the catalytic subunit Esa1.

The INO80 subfamily of chromatin remodeling complexes are ATPases, and includes the INO80 and SWR1 complexes.

References

  1. ↑ Matias, PM; Baek, SH; Bandeiras, TM; Dutta, A; Houry, WA; Llorca, O; Rosenbaum, J (2015). "The AAA+ proteins Pontin and Reptin enter adult age: from understanding their basic biology to the identification of selective inhibitors". Frontiers in Molecular Biosciences. 2: 17. doi: 10.3389/fmolb.2015.00017 . PMC   4428354 . PMID   25988184.
  2. 1 2 3 4 Weiske, Jörg; Huber, Otmar (2005-07-15). "The histidine triad protein Hint1 interacts with Pontin and Reptin and inhibits TCF–β-catenin-mediated transcription". Journal of Cell Science. 118 (14): 3117–3129. doi: 10.1242/jcs.02437 . ISSN   0021-9533. PMID   16014379.
  3. 1 2 Park, Eun-Jung; Hur, Shin-Kyoung; Kwon, Jongbum (2010-10-15). "Human INO80 chromatin-remodelling complex contributes to DNA double-strand break repair via the expression of Rad54B and XRCC3 genes". Biochemical Journal. 431 (2): 179–187. doi:10.1042/BJ20100988. ISSN   0264-6021. PMID   20687897.
  4. ↑ Queval, Richard; Papin, Christophe; Dalvai, Mathieu; Bystricky, Kerstin; Humbert, Odile (2014-12-05). "Reptin and Pontin Oligomerization and Activity Are Modulated through Histone H3 N-terminal Tail Interaction". Journal of Biological Chemistry. 289 (49): 33999–34012. doi: 10.1074/jbc.M114.576785 . ISSN   0021-9258. PMC   4256336 . PMID   25336637.
  5. ↑ "RUVBL2 - RuvB-like 2 - Homo sapiens (Human) - RUVBL2 gene & protein". www.uniprot.org. Retrieved 2016-11-06.
  6. ↑ Gribun, Anna; Cheung, Kevin L. Y.; Huen, Jennifer; Ortega, Joaquin; Houry, Walid A. (2008-03-07). "Yeast Rvb1 and Rvb2 are ATP-Dependent DNA Helicases that Form a Heterohexameric Complex". Journal of Molecular Biology. 376 (5): 1320–1333. doi:10.1016/j.jmb.2007.12.049. PMID   18234224.
  7. ↑ Gallant, Peter (2007). "Control of Transcription by Pontin and Reptin" (PDF). Trends in Cell Biology. 17 (4, 187–192): 187–192. doi:10.1016/j.tcb.2007.02.005. PMID   17320397.
  8. ↑ Venteicher, Andrew S.; Meng, Zhaojing; Mason, Philip J.; Veenstra, Timothy D.; Artandi, Steven E. (2008-03-21). "Identification of ATPases pontin and reptin as telomerase components essential for holoenzyme assembly". Cell. 132 (6): 945–957. doi:10.1016/j.cell.2008.01.019. ISSN   0092-8674. PMC   2291539 . PMID   18358808.
  9. ↑ Maslon, Magdalena M.; Hrstka, Roman; Vojtesek, Borek; Hupp, Ted R. (2010-12-03). "A Divergent Substrate-Binding Loop within the Pro-oncogenic Protein Anterior Gradient-2 Forms a Docking Site for Reptin". Journal of Molecular Biology. 404 (3): 418–438. doi:10.1016/j.jmb.2010.09.035. hdl: 1842/6477 . PMID   20888340.
  10. ↑ Healy, Alan R.; Houston, Douglas R.; Remnant, Lucy; Huart, Anne-Sophie; Brychtova, Veronika; Maslon, Magda M.; Meers, Olivia; Muller, Petr; Krejci, Adam (2015-04-20). "Discovery of a novel ligand that modulates the protein–protein interactions of the AAA+ superfamily oncoprotein reptin". Chemical Science. 6 (5): 3109–3116. doi: 10.1039/c4sc03885a . ISSN   2041-6539. PMC   5490336 . PMID   28706685.
  11. 1 2 3 Bauer, Andreas; Chauvet, Sophie (2000). "Pontin52 and Reptin52 function as antagonistic regulators of β-catenin signalling activity". The EMBO Journal. 19 (22): 6121–6130. doi:10.1093/emboj/19.22.6121. PMC   305835 . PMID   11080158.
  12. 1 2 3 Rosenbaum, Jean; Baek, Sung Hee; Dutta, Anindya; Houry, Walid A.; Huber, Otmar; Hupp, Ted R.; Matias, Pedro M. (2013-03-12). "The Emergence of the Conserved AAA ATPases Pontin and Reptin on the Signaling Landscape". Science Signaling. 6 (266): mr1. doi:10.1126/scisignal.2003906. PMC   4201591 . PMID   23482663.
  13. ↑ Jacquet, Karine; Fradet-Turcotte, Amélie; Avvakumov, Nikita; Lambert, Jean-Philippe; Roques, Céline; Pandita, Raj K.; Paquet, Eric; Herst, Pauline; Gingras, Anne-Claude (2016-05-05). "The TIP60 complex regulates bivalent chromatin recognition by 53BP1 through direct H4K20me binding and H2AK15 acetylation". Molecular Cell. 62 (3): 409–421. doi:10.1016/j.molcel.2016.03.031. ISSN   1097-2765. PMC   4887106 . PMID   27153538.
  14. ↑ Qi, Dai; Jin, Haining; Lilja, Tobias; Mannervik, Mattias (2016-11-07). "Drosophila Reptin and Other TIP60 Complex Components Promote Generation of Silent Chromatin". Genetics. 174 (1): 241–251. doi:10.1534/genetics.106.059980. ISSN   0016-6731. PMC   1569795 . PMID   16816423.
  15. ↑ Stolc, Viktor; et al. (2005). "Genome-wide transcriptional analysis of flagellar regeneration in Chlamydomonas reinhardtii identifies orthologs of ciliary disease genes". PNAS. 102 (10): 3703–3707. Bibcode:2005PNAS..102.3703S. doi: 10.1073/pnas.0408358102 . PMC   553310 . PMID   15738400.
  16. ↑ Zhao, Lu; Yuan, Shiaulou; Cao, Ying; Kallakuri, Sowjanya; Li, Yuanyuan; Kishimoto, Norihito; DiBella, Linda; Sun, Zhaoxia (2013-07-30). "Reptin/Ruvbl2 is a Lrrc6/Seahorse interactor essential for cilia motility". Proceedings of the National Academy of Sciences of the United States of America. 110 (31): 12697–12702. Bibcode:2013PNAS..11012697Z. doi: 10.1073/pnas.1300968110 . ISSN   0027-8424. PMC   3732945 . PMID   23858445.
  17. 1 2 Kakihara, Yoshito; Houry, Walid A. (2012-01-01). "The R2TP complex: Discovery and functions". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. AAA ATPases: structure and function. 1823 (1): 101–107. doi: 10.1016/j.bbamcr.2011.08.016 . PMID   21925213.
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