Alan Lambowitz | |
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| Born | December 24, 1947 Brooklyn, New York, United States |
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Alan Lambowitz is a professor for the University of Texas at Austin in Molecular Biosciences and Oncology and has been instrumental in many bio-molecular processes and concepts, such as intron splicing and mitochondrial ribosomal assembly. [1]
Alan Lambowitz was born in Brooklyn, New York on December 24, 1947. Growing up he attended Stuyvesant High School, a school specialized in science. Following high school, he attended Brooklyn College for his undergraduate degree in Chemistry. Upon completing this degree in 1968, Lambowitz promptly began graduate school at Yale where he continued his love for science in the laboratory. He received a Ph.D. from Yale and then decided to move his work to the Johnson Research Foundation at the University of Pennsylvania. [1]
During his postdoctoral work, Lambowitz investigated a common mechanism of oxidative phosphorylation and discovered that the mechanism was incorrect. Lambowitz once again moved in 1973 to Rockefeller University. Here he had the opportunity to work with David Luck, a prominent name in the discovery of mitochondrial DNA. [2] After a stint at Rockefeller University, Lambowitz pursued a fellowship at the National Institute of Mental Health, followed by an acceptance of a faculty position at St Louis University School of Medicine under the department of biochemistry. [1] Here he took part in work surrounding Neurospora strains and examining the mitochondrial DNA that exists within them. In 1986 Lambowitz took a position with the Ohio Eminent Scholar and Professor of Molecular Genetics and Biochemistry at Ohio State University. A majority of his work here centered around mitochondrial plasmid DNA found within fungal strains. [3] Upon returning to St. Louis, Lambowitz promptly began studying splicing mechanisms of ribosomal RNA processing systems. Although he's not responsible for the discovery of splicing, the research that follows this within the bacterial community can largely be attributed to him, especially when regarding groups 2 introns. [4] Lambowitz made the move to Austin, Texas in 1997 becoming the director of The Institute for Cellular and Molecular Biology there. Here he has cultivated a group of professionals that work on molecular biological research and received multiple merit awards in the process. [5] [3]
Lambowitz graduated Summa cum laude with honors from Brooklyn College. [1] In 1995 he was named a Fellow of the American Academy of Arts and Sciences. [1] Following this in 2001 he was named a Fellow within the American Association for the Advancement of Science. [1] In 2004, he was named a Fellow of the American Academy for Microbiology and named a Member of both the National Academy of Sciences and the Academy of Medicine, Engineering and Science of Texas. [1] Most recently he was awarded with the Wilbur Cross Medal by Yale University for his outstanding achievements in scholarship, teaching, academic administration, and public service. [1] [6]
Lambowitz has spent a majority of his career focusing on a very common bacteria known as Neurospora Crassa , or common bread mold. Through utilizing this bacteria as a research specimen, Lambowitz has helped pioneer many new theories as well as discount some older, incorrect theories.
Much of the function of introns is still unknown to the scientific community today. This is precisely why Lambowitz focuses a majority of his research surrounding group 2 introns. [7] [8] Group 2 introns are a specific type of intron that is able to self-spice out of RNA segments and also are able to facilitate splicing and insertion into DNA in order to be replicated and passed on through ancestral pathways. [9] These particular introns are especially important in understanding a variety of concepts within the microbiological community.
Lambowitz focuses on a variety of these concepts while in the lab, such as Group ll Intron reverse transcriptase mechanisms or RNA sequencing. One of the first concepts surrounding group 2 introns that Lambowitz began studying was their size and proliferation within cells. [10] Group 2 introns specifically are often found in bacterial genomes, as well as in chloroplasts and mitochondrial genomes of eukaryotes. It was hypothesized that group 2 introns originated from proteobacteria that were incorporated into host genomes through the process of endosymbiosis. Once in the host genome, these introns went through a degeneration sequence, but promptly proliferated in large amounts after this degeneration. This allowed for the creation of an intron rich environment. Lambowitz and colleagues were able to determine that group 2 introns specifically were a longer form of intron, especially in ancestral form. This is specific to group 2 introns and is thought to be a result of their self-splicing mechanisms. Lambowitz furthered his research into group 2 introns, specifically exploring how these introns could help tell the story of ancestral bacterial lines using RNA sequencing. [11] Along with colleagues, Lambowitz discovered that group 2 introns use a specific intron encoded protein in order to self-splice out of RNA. After understanding that these proteins serve to splice introns out of RNA, [12] [13] Lambowitz also discovered that the protein is capable of reverse transcriptase type functions in order to insert introns into host DNA. [14] This discovery was crucial in understanding how these introns carried through ancestral lineage. Also, an important connection to know was the relationship between intron encoded proteins and the size of group 2 introns seen in host cells. When these introns are capable of encoding for their own intron encoded proteins the introns tend to be much longer.
After laying the foundation for group 2 introns and the functions they provide, Lambowitz has branched off into using these mechanisms in order to discover ancestral lineage of bacteria, as well as to pursue research surrounding RNA Diagnostic approaches to disease identification. [15] [16] [17] [18] [19] These aspects are crucial in developing faster disease recognition techniques, therefore saving more lives in the long run.
In genetics, complementary DNA (cDNA) is DNA that was reverse transcribed from an RNA. cDNA exists in both single-stranded and double-stranded forms and in both natural and engineered forms.
An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word intron is derived from the term intragenic region, i.e., a region inside a gene. The term intron refers to both the DNA sequence within a gene and the corresponding RNA sequence in RNA transcripts. The non-intron sequences that become joined by this RNA processing to form the mature RNA are called exons.
RNA splicing is a process in molecular biology where a newly-made precursor messenger RNA (pre-mRNA) transcript is transformed into a mature messenger RNA (mRNA). It works by removing all the introns and splicing back together exons. For nuclear-encoded genes, splicing occurs in the nucleus either during or immediately after transcription. For those eukaryotic genes that contain introns, splicing is usually needed to create an mRNA molecule that can be translated into protein. For many eukaryotic introns, splicing occurs in a series of reactions which are catalyzed by the spliceosome, a complex of small nuclear ribonucleoproteins (snRNPs). There exist self-splicing introns, that is, ribozymes that can catalyze their own excision from their parent RNA molecule. The process of transcription, splicing and translation is called gene expression, the central dogma of molecular biology.
Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be included within or excluded from the final, processed messenger RNA (mRNA) produced from that gene. This means the exons are joined in different combinations, leading to different (alternative) mRNA strands. Consequently, the proteins translated from alternatively spliced mRNAs usually contain differences in their amino acid sequence and, often, in their biological functions.
Ribonuclease H is a family of non-sequence-specific endonuclease enzymes that catalyze the cleavage of RNA in an RNA/DNA substrate via a hydrolytic mechanism. Members of the RNase H family can be found in nearly all organisms, from bacteria to archaea to eukaryotes.
Protein splicing is an intramolecular reaction of a particular protein in which an internal protein segment is removed from a precursor protein with a ligation of C-terminal and N-terminal external proteins on both sides. The splicing junction of the precursor protein is mainly a cysteine or a serine, which are amino acids containing a nucleophilic side chain. The protein splicing reactions which are known now do not require exogenous cofactors or energy sources such as adenosine triphosphate (ATP) or guanosine triphosphate (GTP). Normally, splicing is associated only with pre-mRNA splicing. This precursor protein contains three segments—an N-extein followed by the intein followed by a C-extein. After splicing has taken place, the resulting protein contains the N-extein linked to the C-extein; this splicing product is also termed an extein.
Marlene Belfort is an American biochemist known for her research on the factors that interrupt genes and proteins. She is a fellow of the American Academy of Arts and Sciences and has been admitted to the United States National Academy of Sciences.
Exon shuffling is a molecular mechanism for the formation of new genes. It is a process through which two or more exons from different genes can be brought together ectopically, or the same exon can be duplicated, to create a new exon-intron structure. There are different mechanisms through which exon shuffling occurs: transposon mediated exon shuffling, crossover during sexual recombination of parental genomes and illegitimate recombination.
Multicopy single-stranded DNA (msDNA) is a type of extrachromosomal satellite DNA that consists of a single-stranded DNA molecule covalently linked via a 2'-5'phosphodiester bond to an internal guanosine of an RNA molecule. The resultant DNA/RNA chimera possesses two stem-loops joined by a branch similar to the branches found in RNA splicing intermediates. The coding region for msDNA, called a "retron", also encodes a type of reverse transcriptase, which is essential for msDNA synthesis.
Group II introns are a large class of self-catalytic ribozymes and mobile genetic elements found within the genes of all three domains of life. Ribozyme activity can occur under high-salt conditions in vitro. However, assistance from proteins is required for in vivo splicing. In contrast to group I introns, intron excision occurs in the absence of GTP and involves the formation of a lariat, with an A-residue branchpoint strongly resembling that found in lariats formed during splicing of nuclear pre-mRNA. It is hypothesized that pre-mRNA splicing may have evolved from group II introns, due to the similar catalytic mechanism as well as the structural similarity of the Group II Domain V substructure to the U6/U2 extended snRNA. Finally, their ability to site-specifically insert into DNA sites has been exploited as a tool for biotechnology. For example, group II introns can be modified to make site-specific genome insertions and deliver cargo DNA such as reporter genes or lox sites
Geobacillus stearothermophilus is a rod-shaped, Gram-positive bacterium and a member of the phylum Bacillota. The bacterium is a thermophile and is widely distributed in soil, hot springs, ocean sediment, and is a cause of spoilage in food products. It will grow within a temperature range of 30 to 75 °C. Some strains are capable of oxidizing carbon monoxide aerobically. It is commonly used as a challenge organism for sterilization validation studies and periodic check of sterilization cycles. The biological indicator contains spores of the organism on filter paper inside a vial. After sterilizing, the cap is closed, an ampule of growth medium inside of the vial is crushed and the whole vial is incubated. A color and/or turbidity change indicates the results of the sterilization process; no change indicates that the sterilization conditions were achieved, otherwise the growth of the spores indicates that the sterilization process has not been met. Recently a fluorescent-tagged strain, Rapid Readout(tm), is being used for verifying sterilization, since the visible blue fluorescence appears in about one-tenth the time needed for pH-indicator color change, and an inexpensive light sensor can detect the growing colonies.
The homing endonucleases are a collection of endonucleases encoded either as freestanding genes within introns, as fusions with host proteins, or as self-splicing inteins. They catalyze the hydrolysis of genomic DNA within the cells that synthesize them, but do so at very few, or even singular, locations. Repair of the hydrolyzed DNA by the host cell frequently results in the gene encoding the homing endonuclease having been copied into the cleavage site, hence the term 'homing' to describe the movement of these genes. Homing endonucleases can thereby transmit their genes horizontally within a host population, increasing their allele frequency at greater than Mendelian rates.
Group I introns are large self-splicing ribozymes. They catalyze their own excision from mRNA, tRNA and rRNA precursors in a wide range of organisms. The core secondary structure consists of nine paired regions (P1-P9). These fold to essentially two domains – the P4-P6 domain and the P3-P9 domain. The secondary structure mark-up for this family represents only this conserved core. Group I introns often have long open reading frames inserted in loop regions.
A retron is a distinct DNA sequence found in the genome of many bacteria species that codes for reverse transcriptase and a unique single-stranded DNA/RNA hybrid called multicopy single-stranded DNA (msDNA). Retron msr RNA is the non-coding RNA produced by retron elements and is the immediate precursor to the synthesis of msDNA. The retron msr RNA folds into a characteristic secondary structure that contains a conserved guanosine residue at the end of a stem loop. Synthesis of DNA by the retron-encoded reverse transcriptase (RT) results in a DNA/RNA chimera which is composed of small single-stranded DNA linked to small single-stranded RNA. The RNA strand is joined to the 5′ end of the DNA chain via a 2′–5′ phosphodiester linkage that occurs from the 2′ position of the conserved internal guanosine residue.
Numerous key discoveries in biology have emerged from studies of RNA, including seminal work in the fields of biochemistry, genetics, microbiology, molecular biology, molecular evolution, and structural biology. As of 2010, 30 scientists have been awarded Nobel Prizes for experimental work that includes studies of RNA. Specific discoveries of high biological significance are discussed in this article.
Maturase K (matK) is a plant plastidial gene. The protein it encodes is an organelle intron maturase, a protein that splices Group II introns. It is essential for in vivo splicing of Group II introns. Amongst other maturases, this protein retains only a well conserved domain X and remnants of a reverse transcriptase domain.
Prp8 refers to both the Prp8 protein and Prp8 gene. Prp8's name originates from its involvement in pre-mRNA processing. The Prp8 protein is a large, highly conserved, and unique protein that resides in the catalytic core of the spliceosome and has been found to have a central role in molecular rearrangements that occur there. Prp8 protein is a major central component of the catalytic core in the spliceosome, and the spliceosome is responsible for splicing of precursor mRNA that contains introns and exons. Unexpressed introns are removed by the spliceosome complex in order to create a more concise mRNA transcript. Splicing is just one of many different post-transcriptional modifications that mRNA must undergo before translation. Prp8 has also been hypothesized to be a cofactor in RNA catalysis.
The split gene theory is a theory of the origin of introns, long non-coding sequences in eukaryotic genes between the exons. The theory holds that the randomness of primordial DNA sequences would only permit small (< 600bp) open reading frames (ORFs), and that important intron structures and regulatory sequences are derived from stop codons. In this introns-first framework, the spliceosomal machinery and the nucleus evolved due to the necessity to join these ORFs into larger proteins, and that intronless bacterial genes are less ancestral than the split eukaryotic genes. The theory originated with Periannan Senapathy.
Constructive neutral evolution(CNE) is a theory that seeks to explain how complex systems can evolve through neutral transitions and spread through a population by chance fixation (genetic drift). Constructive neutral evolution is a competitor for both adaptationist explanations for the emergence of complex traits and hypotheses positing that a complex trait emerged as a response to a deleterious development in an organism. Constructive neutral evolution often leads to irreversible or "irremediable" complexity and produces systems which, instead of being finely adapted for performing a task, represent an excess complexity that has been described with terms such as "runaway bureaucracy" or even a "Rube Goldberg machine".
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