Center for Gene Regulation in Health and Disease (GRHD)

Anton Komar

Anton
Dr. Anton A. Komar
Professor and Director of the Center for Gene Regulation in Health and Disease
Location: 
SR 259
Phone: 
216-687-2516
Fax: 
216-687-6972
a.komar@csuohio.edu

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

Some of the key publications:

Komar AA, Kommer A, Krasheninnikov IA, Spirin AS. (1997) Cotranslational folding of globin. J Biol Chem. 272, 10646-10651

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

Komar AA, Lesnik T, Cullin C, Merrick WC, Trachsel H, 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 AA, Gross SR, Barth-Baus D, Strachan R, Hensold JO, Goss Kinzy T, Merrick WC. (2005) Novel characteristics of the biological properties of the yeast Saccharomyces cerevisiae eukaryotic initiation factor 2A. J Biol Chem. 280, 15601-15611.

Komar AA. (2007) SNPs, silent but not invisible. Science, 315, 466-467.

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

Holtkamp W, Kokic G, Jäger M, Mittelstaet J, Komar AA, Rodnina MV. (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 MV, Komar AA. (2016) Synonymous codons direct cotranslational folding toward different protein conformations. Mol. Cell., 61, 341-351.

Komar AA. (2016) The yin and yang of codon usage. Hum Mol Genet., 25(R2), R77-R85.

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. (2021) Reduced life span and metabolic syndrome phenotype in eIF2A-knockout mouse model. FASEB J, 35, e21990.

Other recent representative publications in reverse chronological order:

Mazumder B, Komar AA, Cis regulatory elements: A novel communication route between the host cell and the SARS-CoV-2 genome, in Thematic Approaches to COVID-19: Structure, transmission and avoidance, 2023, Rajendram, R., Martin, C. R., Patel, V. B., Preedy, V. R. (Editors). Academic Press/Elsevier, Cambridge,MA, USA.

Fumagalli SE, Padhiar NH, Meyer D, Katneni U, Bar H, DiCuccio M, Komar AA, Kimchi-Sarfaty C. Analysis of 3.5 million SARS-CoV-2 sequences reveals unique mutational trends with consistent nucleotide and codon frequencies. Virol J. 2023 Feb 17;20(1):31. doi: 10.1186/s12985-023-01982-8.

Katneni U, Alexaki A, Hunt R, Katagiri N, Hettiarachchi G, Kames J, McGill JR, Holcomb DDF, Athey J, Lin B, Parunov LA, Kafri T, Lu Q, Peters RT, Ovanesov MV, Freedberg D, Bar H, Komar AA, Sauna ZE, Kimchi-Sarfaty C. Structural, functional, and immunogenicity implications of F9 gene recoding. Blood Adv. 2022 Apr 12:bloodadvances.2022007094. doi: 10.1182/bloodadvances. 2022007094.

Basu A, Penumutchu S, Nguyen K, Tolbert BS, Karn J, Komar AA, Mazumder B. A structurally conserved RNA element within SARS-CoV-2 ORF1a RNA and S mRNA regulates translation in response to viral S protein-induced signaling in human lung cells. J. Virol. 2022 Jan 26;96(2):e0167821. doi: 10.1128/JVI.01678-21. Epub 2021 Nov 10.

Komar AA. A code within a code: how codons fine-tune protein folding in the cell. Biochemistry, 2021, Aug;86(8):976-991. doi: 10.1134/S0006297921080083. PMID: 34488574.

Komar AA., Merrick WC. A retrospective on eIF2A – and not the alpha subunit of eIF2. Int J Mol Sci. 2020, Mar 17;21(6):2054. doi: 10.3390/ijms21062054. PMID: 32192132.

Komar AA. Synonymous Codon Usage – a Guide for Co-translational Protein Folding in the Cell. Mol. Biol., 2019 Nov-Dec;53(6):883-898. doi: 10.1134/S0026898419060090. PMID: 31876270.

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. Effects of codon optimization on coagulation factor IX translation and structure: Implications for protein and gene therapies. Sci Rep. 2019 Oct 29;9(1):15449. doi: 10.1038/s41598-019-51984-2. PMID: 31664102.

Singh N, Jindal S, Ghosh A, Komar AA. Communication between RACK1/Asc1 and uS3 (Rps3) is essential for RACK1/Asc1 function in yeast Saccharomyces cerevisiae. Gene 2019 Jul 20;706:69-76. doi: 10.1016/j.gene.2019.04.087. PMID: 31054365.

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. Codon and Codon-Pair Usage Tables (CoCoPUTs): Facilitating Genetic Variation Analyses and Recombinant Gene Design. J Mol Biol. 2019 Jun 14;431(13):2434-2441. doi: 10.1016/j.jmb.2019.04.02. PMID: 31029701.

Jindal S, Ghosh A, Singh N, Komar AA. Role of uS9/yS16 C-terminal tail in translation initiation and elongation in yeast Saccharomyces cerevisiae. Nucleic Acids Res. 2019 Jan 25;47(2):806-823. doi: 10.1093/nar/gky1180. PMID: 30481328.

Zinoviev, A. Goyal, A., Jindal, S., LaCava, J, Komar, AA, Rodnina, MV, Hellen, CUT, Pestova, TV. Functions of unconventional mammalian translational GTPases GTPBP1 and GTPBP2. Genes Dev. 2018 Sep 1;32(17-18):1226-1241. doi: 10.1101/gad.314724.118. Epub 2018 Aug 14. PMID: 30108131.

 Arndt, N., Ross-Kaschitza D, Kojukhov A, Komar AA. Altmann M. Properties of the ternary complex formed by yeast 1 eIF4E, p20 and mRNA. Sci Rep., 2018 Apr 30;8(1):6707. doi: 10.1038/s41598-018-25273-3. PMID: 29712996. 

Komar AA. Unraveling co-translational protein folding: concepts and methods. Methods, 2017, S1046-2023(17)30273-6. doi: 10.1016/j.ymeth.2017.11.007. PMID: 29221924.

Basu A, Wells N, Tolbert BS, Komar AA, Mazumder B. Conserved structures formed by heterogeneous RNA sequences drive silencing of an inflammation responsive post transcriptional operon. Nucleic Acids Res. 2017, 45(22):12987-13003. doi: 10.1093/nar/gkx979. PMID: 29069516.

Guan B-J, van Hoef V, Jobava R, Elroy-Stein O, Valasek LS, Cargnello M, Gao X-H, Krokowski D, Merrick WC, Kimball SR, Komar AA, Koromilas AE, Wynshaw-Boris A, Topisirovic I, Larsson O, Hatzoglou M. A Unique ISR Program Determines Cellular Responses to Chronic Stress. Mol Cell, 2017, 68(5):885-900.e6. doi: 10.1016/j.molcel.2017.11.007. PMID: 29220654

Simhadri VL, Katagiri NH, Lin BC, Hunt R, Jha S, Tseng SC, Wu A,  Bentley AA, Zichel R, Lu Q, Zhu L, Freedberg DI, Monroe DM, Sauna ZE, Peters R, Komar AA, Kimchi-Sarfaty C. Single synonymous mutation in Factor IX alters protein properties and underlies hemophilia B. J Med Genet, 2017 Dec 22. pii: jmedgenet-2016-104072. doi: 10.1136/jmedgenet-2016-104072. PMID: 28007939.

Golovko A, Kojukhov A., Guan B-J, Morpurgo B, Merrick WC, Mazumder B, Hatzoglou M, Komar AA. The eIF2A knockout mouse. Cell Cycle, 2016 Nov 16;15(22):3115-3120. PMID: 27686860.

Komar AA. The art of gene redesign and recombinant protein production: approaches and perspectives. Top. Med. Chem., 2016, 2, 1-17.

Ghosh A, Jindal S, Bentley AA, Hinnebusch AG, Komar AA. Rps5-Rps16 communication is essential for efficient translation initiation in yeast S. cerevisiae. Nucleic Acids Res. 2014 Jul;42(13):8537-55. doi: 10.1093/nar/gku550. Epub 2014 Jun 19. PubMed PMID: 24948608; PubMed Central PMCID: PMC4117775.