Center for Gene Regulation in Health and Disease (GRHD)

Anton Komar

Professor and Director of the Center for Gene Regulation in Health and Disease
SR 259

We are interested in investigation of protein synthesis, co-translational protein folding and translational control of gene expression in eukaryotic cells.

Research in the laboratory has several major foci:

We are interested in protein structure/function relationships and the mechanism of protein synthesis and translational control of gene expression in eukaryotic cells. Regulation of mRNA translation is an important step in the control of gene expression. Regulation of translation is mainly exerted at the initiation step of protein synthesis, thus allowing rapid modification of the overall rate of translation as well as post-transcriptional regulation of gene expression due to changes in the relative selection of different mRNA species utilizing different mechanisms of translation initiation. Over the past decade, research in this field has revealed numerous new control mechanisms and new ones are constantly being added to the list along with their translationally regulated genes. Translational control plays a pivotal role in development, differentiation, cell cycle progression, cell growth, apoptosis, and stress. As such, dysregulation of translation has been shown to be associated with a wide range of human diseases, including but not limited to diabetes and cancer.
Initiation of protein synthesis in eukaryotes is a complex process requiring more than 12 different initiation factors, comprising over 30 polypeptide chains. The functions of many of these factors have been established in detail; however, the precise role of some of them and their mechanism of action are still not well understood.
We are currently focusing our efforts on understanding the structure and function of eukaryotic initiation factor eIF2A, that does not function in major steps in the initiation process, but is believed to act at some minor/alternative initiation events such as reinitiation, internal initiation, or non-AUG initiation, important for translational control of specific mRNAs. 

The research in the laboratory is further devoted to the co-translational protein folding and the impact of synonymous mutations on gene function and phenotype. The journey of nascent polypeptides from synthesis at the peptidyl transferase center of the ribosome  to full function involves multiple interactions, constraints, modifications and folding events. Each step of this journey impacts the ultimate expression level and functional capacity of the translated protein. It has become clear that the kinetics of protein translation is predominantly modulated by synonymous codon usage along the mRNA, and that this provides an active mechanism for coordinating the synthesis, maturation and folding of nascent polypeptides. 


Complete List of Published Work in MyBibliography

Representative publications:

Krasheninnikov I.A., Komar A.A. and Adzhubei I.A. (1991) Nonuniform size distribution of nascent globin peptides, evidence for pause localization sites, and a cotranslational protein-folding model. J. Prot. Chem., 10, 445-454.

Komar A.A., Kommer A., Krasheninnikov I.A. and Spirin A.S. (1993) Cotranslational heme binding to nascent globin chains. FEBS Letters, 326, 261-263.

Komar A.A. and Jaenicke R. (1995) Kinetics of translation of gamma-B crystallin and its circularly permutated variant in an in vitro cell-free system: possible relations to codon distribution and protein folding. FEBS Letters, 376, 195-198.

Komar A.A., Kommer A., Krasheninnikov I.A. and Spirin A.S. (1997) Cotranslational folding of globin. J. Biol. Chem., 272, 10646-10651.

Komar A.A., Lesnik T. and Reiss C. (1999) Synonymous codon substitutions affect ribosome traffic and protein folding during in vitro translation. FEBS Letters, 462, 387-391.

Thual C., Komar A.A., Bousset L., Fernandez-Bellot E., Cullin C. and Melki R (1999) Structural characterization of Saccharomyces cerevisiae prion-like protein Ure2. J. Biol. Chem., 274, 13666-13614.

Komar A.A., Lesnik T., Cullin C., Merrick W.C., Trachsel H. and Altmann M. (2003) Internal initiation drives the synthesis of Ure2 protein lacking the prion domain and affects [URE3] propagation in yeast cells. EMBO J., 22, 1199-1209.

Komar A.A., Gross S., Barth-Baus D., Strachan R., Hensold J.O., Kinzy T. and Merrick W.C. (2005) Novel characteristics of the biological properties of the yeast Saccharomyces cerevisae initiation factor eIF2A. J. Biol. Chem. 280, 15601-15611.

Komar A.A. and Hatzoglou M. (2005) Internal Ribosome Entry Sites in cellular mRNAs: Mystery of their existence. J. Biol. Chem. 280, 23425-23428.

Komar A.A. (2007) SNPs, Silent But Not Invisible. Science, 315, 466-467.

Komar A.A. (2007) Silent SNPs; impact on gene function and phenotype. Pharmacogenomics, 8, 1075-1080.

Galkin O., Bentley A.A., Gupta S., Toth B-A., Mazumder B., Kinzy T.G. Merrick W.C., Hatzoglou M., Pestova T.V., Hellen C.U.T. and Komar, A.A. (2007) Possible roles of the negatively charged N-terminal extension of Saccharomyces cerevisiae ribosomal protein S5 revealed by characterization of a yeast strain containing human ribosomal protein S5. RNA, 13, 2116-2128.

Pisareva V.P., Pisarev A.V., Komar A.A., Hellen C.U.T., Pestova T.V. (2008) Efficient translation initiation on mammalian mRNAs with structured 5'-UTRs requires DExH-box protein DHX29. Cell, 135, 1237-1250.

Komar A.A. (2009) A pause for thought along the co-translational folding pathway. Trends Biochem. Sci. 34, 16-24.

Lumsden T., Bentley A.A., Beutler W., Ghosh A., Galkin O., and Komar A.A. (2010) Yeast strains with N-terminally truncated ribosomal protein S5; implications for the evolution, structure and function of the Rps5/Rps7 proteins. Nucleic Acids Res. 38, 1261-1272.

Skabkin M.A., Skabkina O.V., Dhote V., Komar A.A., Hellen C.U. and Pestova TV. (2010) Activities of Ligatin and MCT-1/DENR in eukaryotic translation initiation and ribosomal recycling. Genes Dev. 24, 1787-1801.

Gasparian A.V., Neznanov N., Jha. S., Galkin O., Moran J.J., Gudkov A.V., Gurova K.V., and Komar A.A. (2010) Inhibition of EMCV and poliovirus replication by quinacrine: implications for the design and discovery of novel anti-viral drugs. J. Virol. 18, 9390-9397.

Komar, A.A. and Hatzoglou, M. (2011) Cellular IRES-mediated translation: the war of ITAFs in pathophysiological states. Cell Cycle, 10, 229-240.

Jha, S. and Komar, A.A. (2011) Birth, life and death of nascent polypeptide chains. Biotechnol. J., 6, 623-640.

Komar, A.A. Mazumder, B, and Merrick, WC. (2012) A New Framework for Understanding IRES-mediated translation. Gene, 502, 75-86.

Bentley, A.A. Merkulov, S.M., Peng, Y., Rozmarynowycz, R., Qi, X., Pusztai-Carey, M., Merrick, W.C., Yee, V., McCrae, K.R., and Komar, A.A. (2012) Chimeric glutathione S-transferases containing inserts of kininogen peptides: potential novel protein therapeutics. J. Biol. Chem. 287, 22142-22150.

Hamasaki-Katagiri, N., Salari, R., Simhadri, V.L., Tseng, S.C., Needlman, E., Edwards, N.C., Sauna, Z.E. Grigoryan, V., Komar, A.A., Przytycka, T.M. and Kimchi-Sarfaty, C. (2012) Analysis of F9 point mutations and their correlation to severity of hemophilia B disease. Hemophilia B, 1-8.

Jha, S. and Komar, A.A. (2012) Using SecM arrest sequence as a tool to isolate ribosome bound polypeptides. J. Vis Exp. 64, 4027.

Edwards, N.C., Perry, A., Blaisdell, A., Kopelman, D.B. Fathke, R. Plum, W., Newell, J., Allen, C.E., Geetha S., Shapiro, A., Okunji, C., Kosti, I., Shomron, N., Grigoryan, V., Sauna, Z.E., Mandel-Gutfreund, Y., Komar, A.A. and Kimchi-Sarfaty, C. (2012). Characterization of coding synonymous and non-synonymous polymorphisms in ADAMTS13 using ex vivo and in silico approaches. PloS One, 7, e38864.

Jha S. and Komar A.A. (2012) Isolation of ribosome bound nascent polypeptides in vitro to identify translational pause sites along mRNA. J. Vis Exp. 65, 4026.

Shaltouki A., Harford T., Komar A.A. and Weyman C.M. (2013) IRES-mediated translation of the pro-apoptotic Bcl2 family member PUMA, Translation, 1, e24391.

Das P., Basu A., Biswas A., Poddar P., Andrews J., Barik S., Komar A.A. and Mazumder B. (2013) Insights into the mechanism of ribosomal incorporation of mammalian L13a protein during ribosome biogenesis. Mol. Cell Biol, 33, 2829-2842.

Gartner J.J., Parker S.C., Prickett T.D., Dutton-Regester K., Stitzel M.L., Lin J.C., Davis S., Simhadri V.L., Jha S., Katagiri N., Gotea V., Teer J.K., Wei X., Morken M.A., Bhanot U.K.; NISC Comparative Sequencing Program, Chen G., Elnitski L.L., Davies M.A., Gershenwald J.E., Carter H., Karchin R., Robinson W., Robinson S., Rosenberg S.A., Collins F.S., Parmigiani G., Komar A.A., Kimchi-Sarfaty C., Hayward N.K., Margulies E.H., Samuels Y. (2013) Whole-genome sequencing identifies a recurrent functional synonymous mutation in melanoma. Proc Natl Acad Sci U S A, 110, 13481-13486.

Hamasaki-Katagiri N., Salari R., Wu A., Qi Y., Schiller T., Filiberto A.C., Schisterman E.F., Komar A.A., Przytycka T.M., Kimchi-Sarfaty C. (2013) A gene-specific method for predicting hemophilia-causing point mutations. J Mol Biol., 425, 4023-4033.

Simhadri V.L., Hamasaki-Katagiri N., Tseng S.C., Bentley A.A., Zichel R., Hershko A.Y., Komar A.A., Kimchi-Sarfaty C. (2014) Factor IX oligomerization underlies reduced activity upon disruption of physiological conditions. Haemophilia, 20, e157-163.

Ghosh A., Jindal S., Bentley A.A., Hinnebusch A.G., Komar A.A. (2014) Rps5-Rps16 communication is essential for efficient translation initiation in yeast S. cerevisiae. Nucleic Acids Res.42, 8537-8555.
Ghosh A., Komar A.A. (2015) Eukaryote-specific extensions in ribosomal proteins of the small subunit: structure and function. Translation, 3, 1, e999576.
Komar A.A., Hatzoglou M. (2015) Exploring Internal Ribosome Entry Sites as Therapeutic Targets. Front Oncol, 5, 233.
Holtkamp W., Kokic G., Jäger M., Mittelstaet J., Komar A.A., Rodnina M.V. (2015) Cotranslational protein folding on the ribosome monitored in real time. Science, 350, 1104-1107.
Buhr F., Jha S., Thommen M., Mittelstaet J., Kutz F., Schwalbe H., Rodnina M.V., Komar A.A. (2016) Synonymous codons direct cotranslational folding toward different protein conformations. Mol Cell, 61, 341-351.
Komar A.A. (2016) The art of gene redesign and recombinant protein production: approaches and perspectives. Top. Med. Chem. 2, 1-17.
Komar A.A. (2016) The yin and yang of codon usage. Hum Mol Genet., 25(R2), R77-R85.
Golovko A., Kojukhov A., Guan B.J., Morpurgo B., Merrick W.C., Mazumder B., Hatzoglou M., Komar A.A. (2016) The eIF2A knockout mouse.
Cell Cycle. 29, 1-6.
Hamasaki-Katagiri N., Lin B.C., Simon J., Hunt R.C., Schiller T., Russek-Cohen E., Komar A.A., Bar H., Kimchi-Sarfaty C. (2017) The importance of mRNA structure in determining the pathogenicity of synonymous and non-synonymous mutations in haemophilia. Haemophilia, 23, e8-e17.
Simhadri V.L., Hamasaki-Katagiri N., Lin B.C., Hunt R., Jha S., Tseng S.C., Wu A., Bentley A.A., Zichel R., Lu Q., Zhu L., Freedberg D.I., Monroe D.M., Sauna Z.E., Peters R., Komar A.A., Kimchi-Sarfaty C. (2017) Single synonymous mutation in factor IX alters protein properties and underlies haemophilia B. J Med Genet., 54, 338-345.
Basu A., Jain N., Tolbert B.S., Komar A.A., Mazumder B. (2017) Conserved structures formed by heterogeneous RNA sequences drive silencing of an inflammation responsive post-transcriptional operon. Nucleic Acids Res., 45, 12987-13003.
Guan B.J., van Hoef V., Jobava R., Elroy-Stein O., Valasek L.S., Cargnello M., Gao X.H., Krokowski D., Merrick W.C., Kimball S.R., Komar A.A., Koromilas A.E., Wynshaw-Boris A., Topisirovic I., Larsson O., Hatzoglou M. (2017) A Unique ISR Program Determines Cellular Responses to Chronic Stress. Mol Cell, 68, 885-900.
Komar A.A. (2018) Unraveling co-translational protein folding: Concepts and methods. Methods, 137, 71-81.
Arndt N., Ross-Kaschitza D., Kojukhov A., Komar A.A., Altmann M. (2018) Properties of the ternary complex formed by yeast eIF4E, p20 and mRNA. Sci Rep., 8, 6707.
Yehia L., Jindal S., Komar A.A., Eng C. (2018) Non-Canonical Role of Cancer-Associated Mutant SEC23B in the Ribosome Biogenesis Pathway.
Hum Mol Genet., 27, 3154-3164.
Zinoviev, A. Goyal, A., Jindal, S., LaCava, J, Komar, AA, Rodnina, MV, Hellen, CUT, Pestova, TV. (2018) Functions of unconventional mammalian translational GTPases GTPBP1 and GTPBP2. Genes Dev. 32, 1226-1241.
Jindal S, Ghosh A, Singh N, Komar AA. (2019) Role of uS9/yS16 C-terminal tail in translation initiation and elongation in yeast Saccharomyces cerevisiae. Nucleic Acids Res., 47, 806-823. 
Alexaki A, Kames J, Holcomb DD, Athey J, Santana-Quintero LV, Lam PVN, Hamasaki-Katagiri N, Osipova E, Simonyan V, Bar H, Komar AA, Kimchi-Sarfaty C. (2019) Codon and Codon-Pair Usage Tables (CoCoPUTs): Facilitating Genetic Variation Analyses and Recombinant Gene Design. J Mol Biol., 431(13):2434-2441.

Singh N, Jindal S, Ghosh A, Komar AA. (2019) Communication between RACK1/Asc1 and uS3 (Rps3) is essential for RACK1/Asc1 function in yeast Saccharomyces cerevisiae. Gene, 706:69-76.

Katneni UK, Liss A, Holcomb D, Katagiri NH, Hunt R, Bar H, Ismail A, Komar AA, Kimchi-Sarfaty C. (2019) Splicing dysregulation contributes to the pathogenicity of several F9 exonic point variants. Mol Genet Genomic Med, 7(8):e840.

Kour R, Komar AA, Mazumder B. (2019) Mutually exclusive amino acid residues of L13a are responsible for its ribosomal incorporation and translational silencing leading to resolution of inflammation. RNA, 25(10):1377-1392.

Alexaki A, Hettiarachchi GK, Athey JC, Katneni UK, Simhadri V, Hamasaki-Katagiri N, Nanavaty P, Lin B, Takeda K, Freedberg D, Monroe D, McGill JR, Peters R, Kames JM, Holcomb DD, Hunt RC, Sauna ZE, Gelinas A, Janjic N, DiCuccio M, Bar H, Komar AA, Kimchi-Sarfaty C. (2019) Effects of codon optimization on coagulation factor IX translation and structure: Implications for protein and gene therapies. Sci Rep. 9(1):15449.

Komar AA. (2019) Synonymous Codon Usage - a Guide for Co-translational Protein Folding in the Cell. Mol. Biol., 53(6):883-898.

Komar AA, Merrick WC. (2020) A retrospective on eIF2A and not the alpha subunit of eIF2. Int J Mol Sci. 21(6):2054.

Mazumder S, Swank V, Komar AA, Johnson JM Tuohy VK (2020) Monoclonal Antibody against Extracellular Domain of Anti-Müllerian Hormone Receptor II for Immunotargeting of Epithelial Ovarian Carcinoma. Oncotarget, 11(20):1894-1910.

Kames J, Holcomb DD, Kimchi O, DiCuccio M, Hamasaki-Katagiri N, Wang T, Komar AA, Alexaki A, Kimchi-Sarfaty C (2020) Sequence analysis of SARS-CoV-2 genome reveals features important for vaccine design. Sci Rep. 2020, Sep 24;10(1):15643.

Alexaki A, Kames J, Hettiarachchi GK, Athey JC, Katneni UK, Hunt RC, Hamasaki-Katagiri N, Holcomb DD, DiCuccio M, Bar H, Komar AA, Kimchi-Sarfaty C. (2020) Ribosome profiling of HEK293T cells overexpressing codon optimized coagulation factor IX. F1000Res. Mar 10;9:174.

Holcomb D, Alexaki A, Hernandez N, Laurie K, Kames J, Hamasaki-Katagiri N, Komar AA, DiCuccio M, Kimchi-Sarfaty C. Gene variants of coagulation related proteins that interact with SARS-CoV-2. (2021) PLOS Comput. Biol., Mar 17;17(3):e1008805. 

Llerena Cari E, Hagen-Lillevik S, Giornazi A, Post M, Komar AA, Appiah L, Bitler B, Polotsky AJ, Santoro N, Kieft J, Lai K, Johnson J. Integrated stress response control of granulosa cell translation and proliferation during normal ovarian follicle development. (2021) Mol Hum Reprod. Aug 7;27(8):gaab050.

Meyer D, Kames J, Bar H, Komar AA, Alexaki A, Ibla J, Hunt RC, Santana-Quintero LV, Golikov A, DiCuccio M, Kimchi-Sarfaty C. (2021) Distinct signatures of codon and codon pair usage in 32 primary tumor types in the novel database CancerCoCoPUTs for cancer-specific codon usage. Genome Medicine, Jul 28;13(1):122.

Komar AA. (2021) A code within a code: how codons fine-tune protein folding in the cell. Biochemistry (Moscow), Aug;86(8):976-991.

Trainor BM, Komar AA, Pestov DG, Shcherbik  N. (2021) Cell-free Translation: Preparation and Validation of Translation-competent Extracts from Saccharomyces cerevisiae. Bio-protocol, 11(18): e4093.    

Anderson R, Agarwal A, Ghosh A, Guan B-J, Casteel, J., Dvorina N, Baldwin WM, 3rd, Merrick WC, Mazumder B, Buchner D, Hatzoglou M, Kondratov RV, Komar AA. Reduced life span and metabolic syndrome phenotype in eIF2A-knockout mouse model. FASEB J, 2021,