Marilyn Kozak

Last updated
Marilyn S. Kozak
Born (1943-07-08) July 8, 1943 (age 80)
Akron, Ohio, US
Alma mater Johns Hopkins University
Known for Kozak consensus sequence
Scientific career
Fields Microbiology
Institutions Robert Wood Johnson Medical School
Doctoral advisor Daniel Nathans
Other academic advisors Aaron Shatkin

Marilyn S. Kozak is an American professor of biochemistry at the Robert Wood Johnson Medical School. She was previously at the University of Medicine and Dentistry of New Jersey before the school was merged. She was awarded a PhD in microbiology by Johns Hopkins University studying the synthesis of the Bacteriophage MS2, advised by Daniel Nathans. [1] [2] In her original faculty job proposal, she sought to study the mechanism of eukaryotic translation initiation, a problem long thought to have already been solved by Joan Steitz. [3] While in the Department of Biological Sciences at University of Pittsburgh, she published a series of studies that established the scanning model of translation initiation and the Kozak consensus sequence. [4] [5] [6] Her current research interests are unknown as her last publication was in 2008. [7]

Contents

Recognition

Marilyn Kozak was listed as one of the top 10 Women Scientists of the 80's in an article published by The Scientist. This was awarded based on the number of citations for their published work between 1981-1988. During this time, Kozak had 3,107 citations. [4] Her most cited work was from 1984, entitled "Compilation and analysis of sequences upstream from the translational start site in eukaryotic mRNAs". [8] This paper highlighted the research that brought the known cellular mRNAs from 32 to 166.

Controversy

In March 2001, Kozak published a mini-review in the Journal of Molecular and Cellular Biology entitled "New Ways of Initiating Translation in Eukaryotes?" that resulted in push-back from the scientific community. [9] In her publication, Kozak discussed her hesitation towards the role of cellular internal ribosome entry sites (IRES). This was most heavily refuted by Robert Schneider, who published a response article of the same name in the same Journal in Dec. 2001. [10] In this response, Schneider claimed that in publishing her mini-review, Kozak hoped to increase the validity of her own findings. He further stated that Kozak's publication was not up to scholarly standards and should not have been accepted into the Journal of Molecular and Cellular Biology. [10] The existence of cellular IRESes remains controversial. [11] [12] [13]


Contributions

Along with her published work, Kozak has contributed to the scientific community with her role on the editorial board for the Journal of Molecular and Cellular Biology. She has been listed intermittently as an editor between the years 1983-1991. [14] [15] [16]

Selected works

This is a selection of Kozak's work but not a complete list.

Related Research Articles

<span class="mw-page-title-main">Messenger RNA</span> RNA that is read by the ribosome to produce a protein

In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.

<span class="mw-page-title-main">Ribosome</span> Intracellular organelle consisting of RNA and protein functioning to synthesize proteins

Ribosomes are macromolecular machines, found within all cells, that perform biological protein synthesis. Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to form polypeptide chains. Ribosomes consist of two major components: the small and large ribosomal subunits. Each subunit consists of one or more ribosomal RNA (rRNA) molecules and many ribosomal proteins. The ribosomes and associated molecules are also known as the translational apparatus.

<span class="mw-page-title-main">Translation (biology)</span> Cellular process of protein synthesis

In biology, translation is the process in living cells in which proteins are produced using RNA molecules as templates. The generated protein is a sequence of amino acids. This sequence is determined by the sequence of nucleotides in the RNA. The nucleotides are considered three at a time. Each such triple results in addition of one specific amino acid to the protein being generated. The matching from nucleotide triple to amino acid is called the genetic code. The translation is performed by a large complex of functional RNA and proteins called ribosomes. The entire process is called gene expression.

The 5′ untranslated region is the region of a messenger RNA (mRNA) that is directly upstream from the initiation codon. This region is important for the regulation of translation of a transcript by differing mechanisms in viruses, prokaryotes and eukaryotes. While called untranslated, the 5′ UTR or a portion of it is sometimes translated into a protein product. This product can then regulate the translation of the main coding sequence of the mRNA. In many organisms, however, the 5′ UTR is completely untranslated, instead forming a complex secondary structure to regulate translation.

The Shine–Dalgarno (SD) sequence is a ribosomal binding site in bacterial and archaeal messenger RNA, generally located around 8 bases upstream of the start codon AUG. The RNA sequence helps recruit the ribosome to the messenger RNA (mRNA) to initiate protein synthesis by aligning the ribosome with the start codon. Once recruited, tRNA may add amino acids in sequence as dictated by the codons, moving downstream from the translational start site.

An internal ribosome entry site, abbreviated IRES, is an RNA element that allows for translation initiation in a cap-independent manner, as part of the greater process of protein synthesis. In eukaryotic translation, initiation typically occurs at the 5' end of mRNA molecules, since 5' cap recognition is required for the assembly of the initiation complex. The location for IRES elements is often in the 5'UTR, but can also occur elsewhere in mRNAs.

<span class="mw-page-title-main">Start codon</span> First codon of a messenger RNA translated by a ribosome

The start codon is the first codon of a messenger RNA (mRNA) transcript translated by a ribosome. The start codon always codes for methionine in eukaryotes and Archaea and a N-formylmethionine (fMet) in bacteria, mitochondria and plastids.

Bacterial translation is the process by which messenger RNA is translated into proteins in bacteria.

Eukaryotic translation is the biological process by which messenger RNA is translated into proteins in eukaryotes. It consists of four phases: initiation, elongation, termination, and recapping.

The Kozak consensus sequence is a nucleic acid motif that functions as the protein translation initiation site in most eukaryotic mRNA transcripts. Regarded as the optimum sequence for initiating translation in eukaryotes, the sequence is an integral aspect of protein regulation and overall cellular health as well as having implications in human disease. It ensures that a protein is correctly translated from the genetic message, mediating ribosome assembly and translation initiation. A wrong start site can result in non-functional proteins. As it has become more studied, expansions of the nucleotide sequence, bases of importance, and notable exceptions have arisen. The sequence was named after the scientist who discovered it, Marilyn Kozak. Kozak discovered the sequence through a detailed analysis of DNA genomic sequences.

Gene structure is the organisation of specialised sequence elements within a gene. Genes contain most of the information necessary for living cells to survive and reproduce. In most organisms, genes are made of DNA, where the particular DNA sequence determines the function of the gene. A gene is transcribed (copied) from DNA into RNA, which can either be non-coding (ncRNA) with a direct function, or an intermediate messenger (mRNA) that is then translated into protein. Each of these steps is controlled by specific sequence elements, or regions, within the gene. Every gene, therefore, requires multiple sequence elements to be functional. This includes the sequence that actually encodes the functional protein or ncRNA, as well as multiple regulatory sequence regions. These regions may be as short as a few base pairs, up to many thousands of base pairs long.

Eukaryotic initiation factors (eIFs) are proteins or protein complexes involved in the initiation phase of eukaryotic translation. These proteins help stabilize the formation of ribosomal preinitiation complexes around the start codon and are an important input for post-transcription gene regulation. Several initiation factors form a complex with the small 40S ribosomal subunit and Met-tRNAiMet called the 43S preinitiation complex. Additional factors of the eIF4F complex recruit the 43S PIC to the five-prime cap structure of the mRNA, from which the 43S particle scans 5'-->3' along the mRNA to reach an AUG start codon. Recognition of the start codon by the Met-tRNAiMet promotes gated phosphate and eIF1 release to form the 48S preinitiation complex, followed by large 60S ribosomal subunit recruitment to form the 80S ribosome. There exist many more eukaryotic initiation factors than prokaryotic initiation factors, reflecting the greater biological complexity of eukaryotic translation. There are at least twelve eukaryotic initiation factors, composed of many more polypeptides, and these are described below.

A ribosome binding site, or ribosomal binding site (RBS), is a sequence of nucleotides upstream of the start codon of an mRNA transcript that is responsible for the recruitment of a ribosome during the initiation of translation. Mostly, RBS refers to bacterial sequences, although internal ribosome entry sites (IRES) have been described in mRNAs of eukaryotic cells or viruses that infect eukaryotes. Ribosome recruitment in eukaryotes is generally mediated by the 5' cap present on eukaryotic mRNAs.

Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during translation that results in the production of multiple, unique proteins from a single mRNA. The process can be programmed by the nucleotide sequence of the mRNA and is sometimes affected by the secondary, 3-dimensional mRNA structure. It has been described mainly in viruses, retrotransposons and bacterial insertion elements, and also in some cellular genes.

Leaky scanning is a mechanism used during the initiation phase of eukaryotic translation that enables regulation of gene expression. During initiation, the small 40S ribosomal subunit "scans" or moves in a 5' --> 3' direction along the 5'UTR to locate a start codon to commence elongation. Sometimes, the scanning ribosome bypasses the initial AUG start codon and begins translation at further downstream AUG start codons. Translation in eukaryotic cells according to most scanning mechanisms occurs at the AUG start codon proximal to the 5' end of mRNA; however, the scanning ribosome may encounter an “unfavorable nucleotide context” around the start codon and continue scanning.

<span class="mw-page-title-main">Riboregulator</span>

In molecular biology, a riboregulator is a ribonucleic acid (RNA) that responds to a signal nucleic acid molecule by Watson-Crick base pairing. A riboregulator may respond to a signal molecule in any number of manners including, translation of the RNA into a protein, activation of a ribozyme, release of silencing RNA (siRNA), conformational change, and/or binding other nucleic acids. Riboregulators contain two canonical domains, a sensor domain and an effector domain. These domains are also found on riboswitches, but unlike riboswitches, the sensor domain only binds complementary RNA or DNA strands as opposed to small molecules. Because binding is based on base-pairing, a riboregulator can be tailored to differentiate and respond to individual genetic sequences and combinations thereof.

<span class="mw-page-title-main">SUI1</span>

In molecular biology, the single-domain protein SUI1 is a translation initiation factor often found in the fungus, Saccharomyces cerevisiae but it is also found in other eukaryotes and prokaryotes as well as archaea. It is otherwise known as Eukaryotic translation initiation factor 1 (eIF1) in eukaryotes or YciH in bacteria.

Ribosome profiling, or Ribo-Seq, is an adaptation of a technique developed by Joan Steitz and Marilyn Kozak almost 50 years ago that Nicholas Ingolia and Jonathan Weissman adapted to work with next generation sequencing that uses specialized messenger RNA (mRNA) sequencing to determine which mRNAs are being actively translated. A related technique that can also be used to determine which mRNAs are being actively translated is the Translating Ribosome Affinity Purification (TRAP) methodology, which was developed by Nathaniel Heintz at Rockefeller University. TRAP does not involve ribosome footprinting but provides cell type-specific information.

<span class="mw-page-title-main">Ribosomal pause</span> Queueing or stacking of ribosomes during translation of the nucleotide sequence of mRNA transcripts

Ribosomal pause refers to the queueing or stacking of ribosomes during translation of the nucleotide sequence of mRNA transcripts. These transcripts are decoded and converted into an amino acid sequence during protein synthesis by ribosomes. Due to the pause sites of some mRNA's, there is a disturbance caused in translation. Ribosomal pausing occurs in both eukaryotes and prokaryotes. A more severe pause is known as a ribosomal stall.

<span class="mw-page-title-main">Translation regulation by 5′ transcript leader cis-elements</span>

Translation regulation by 5′ transcript leader cis-elements is a process in cellular translation.

References

  1. ↑ Kozak, M; Nathans, D (March 1972). "Translation of the genome of a ribonucleic acid bacteriophage". Bacteriological Reviews. 36 (1): 109–34. doi:10.1128/MMBR.36.1.109-134.1972. PMC   378432 . PMID   4555183.
  2. ↑ Kozak, M; Nathans, D (14 September 1972). "Differential inhibition of coliphage MS2 protein synthesis by ribosome-directed antibiotics". Journal of Molecular Biology. 70 (1): 41–55. doi:10.1016/0022-2836(72)90162-3. PMID   4561347.
  3. ↑ Kozak, Marilyn (4 October 1993). "Identifying AUG Initiator Codons" (PDF). Citation Classic Commentaries. 36 (40). Retrieved 4 July 2015.
  4. 1 2 Grissom, Abigail (15 October 1990). "Research: Top 10 Women Scientists Of The '80s: Making A Difference". The Scientist. Retrieved 4 July 2015.
  5. 1 2 Kozak, M (26 October 1987). "An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs". Nucleic Acids Research. 15 (20): 8125–48. doi:10.1093/nar/15.20.8125. PMC   306349 . PMID   3313277.
  6. ↑ Kozak, M (31 January 1986). "Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes". Cell. 44 (2): 283–92. doi:10.1016/0092-8674(86)90762-2. PMID   3943125. S2CID   15613863.
  7. 1 2 Kozak, Marilyn (2008-11-01). "Faulty old ideas about translational regulation paved the way for current confusion about how microRNAs function". Gene. 423 (2): 108–115. doi:10.1016/j.gene.2008.07.013. ISSN   0378-1119. PMID   18692553.
  8. ↑ Kozak, Marilyn (1984-01-25). "Compilation and analysis of sequences upstream from the translational start site in eukaryotic mRNAs". Nucleic Acids Research. 12 (2): 857–872. doi:10.1093/nar/12.2.857. ISSN   0305-1048. PMC   318541 . PMID   6694911.
  9. ↑ Kozak, Marilyn (2001-03-15). "New Ways of Initiating Translation in Eukaryotes?". Molecular and Cellular Biology. 21 (6): 1899–1907. doi:10.1128/MCB.21.6.1899-1907.2001. ISSN   0270-7306. PMC   86772 . PMID   11238926.
  10. 1 2 Schneider, Robert (2001). "New Ways of Initiating Translation in Eukaryotes?". Molecular and Cellular Biology. 21 (23): 8238–8246. doi:10.1128/MCB.21.23.8238-8246.2001. ISSN   0270-7306. PMC   99989 . PMID   11710333.
  11. ↑ Bert, Andrew (2006). "Assessing IRES activity in the HIF-1alpha and other cellular 5' UTRs". RNA. 12 (6): 1074–1083. doi:10.1261/rna.2320506. PMC   1464860 . PMID   16601206.
  12. ↑ Jackson, Richard (2013). "The Current Status of Vertebrate Cellular mRNA IRESs". Cold Springs Harbor Perspectives in Biology. 5 (2): a011569. doi:10.1101/cshperspect.a011569. PMC   3552511 . PMID   23378589.
  13. ↑ Yang, Yun (2019). "TIRES-mediated cap-independent translation, a path leading to hidden proteome". Journal of Molecular Cell Biology. 11 (10): 911–919. doi:10.1093/jmcb/mjz091. PMC   6884710 . PMID   31504667.
  14. ↑ "Molecular and Cellular Biology Editorial Board" (PDF). Journal of Molecular and Cellular Biology. 1983. PMC   368623 .
  15. ↑ "Molecular and Cellular Biology Editorial Board" (PDF). Journal of Molecular and Cellular Biology. 1988.
  16. ↑ "Molecular and Cellular Biology Editorial Board" (PDF). Journal of Molecular and Cellular Biology. 1991.
  17. ↑ Kozak, M. (1991-11-15). "An analysis of vertebrate mRNA sequences: intimations of translational control". The Journal of Cell Biology. 115 (4): 887–903. doi:10.1083/jcb.115.4.887. ISSN   0021-9525. PMC   2289952 . PMID   1955461.
  18. ↑ Kozak, M. (1986-05-01). "Influences of mRNA secondary structure on initiation by eukaryotic ribosomes". Proceedings of the National Academy of Sciences. 83 (9): 2850–2854. Bibcode:1986PNAS...83.2850K. doi: 10.1073/pnas.83.9.2850 . ISSN   0027-8424. PMC   323404 . PMID   3458245.
  19. ↑ Kozak, Marilyn (1987-08-20). "At least six nucleotides preceding the AUG initiator codon enhance translation in mammalian cells". Journal of Molecular Biology. 196 (4): 947–950. doi:10.1016/0022-2836(87)90418-9. ISSN   0022-2836. PMID   3681984.
  20. ↑ Kozak, Marilyn (January 1986). "Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes". Cell. 44 (2): 283–292. doi:10.1016/0092-8674(86)90762-2. ISSN   0092-8674. PMID   3943125. S2CID   15613863.
  21. ↑ Kozak, Marilyn (1981-10-24). "Possible role of flanking nucleotides in recognition of the AUG initiator codon by eukaryotic ribosomes". Nucleic Acids Research. 9 (20): 5233–5252. doi:10.1093/nar/9.20.5233. ISSN   0305-1048. PMC   327517 . PMID   7301588.
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