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David Baltimore

Bio: David Baltimore is an academic researcher from California Institute of Technology. The author has contributed to research in topics: RNA & Virus. The author has an hindex of 203, co-authored 876 publications receiving 162955 citations. Previous affiliations of David Baltimore include Thomas Jefferson University & Johns Hopkins University.


Papers
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Journal ArticleDOI
TL;DR: By the use of the two-hybrid protein interaction system, a human protein that specifically interacts with RAG-1 is isolated, which is the human homologue of the yeast SRP1 (suppressor of a temperature-sensitive RNA polymerase I mutation).
Abstract: Genes for immunoglobulins and T-cell receptor are generated by a process known as V(D)J recombination. This process is highly regulated and mediated by the recombination activating proteins RAG-1 and RAG-2. By the use of the two-hybrid protein interaction system, we isolated a human protein that specifically interacts with RAG-1. This protein is the human homologue of the yeast SRP1 (suppressor of a temperature-sensitive RNA polymerase I mutation). The SRP1-1 mutation is an allele-specific dominant suppressor of a temperature-sensitive mutation in the zinc binding domain of the 190-kDa subunit of Saccharomyces cerevisiae RNA polymerase I. The human SRP cDNA clone was used to screen a mouse cDNA library. We obtained a 3.9-kbp cDNA clone encoding the mouse SRP1. The open reading frame of this cDNA encodes a 538-amino acid protein with eight degenerate repeats of 40-45 amino acids each. The mouse and human SRP1 are 98% identical, while the mouse and yeast SRP1 have 48% identity. After cotransfection of the genes encoding RAG-1 and human SRP1 into 293T cells, a stable complex was evident. Deletion analysis indicated that the region of the SRP1 protein interacting with RAG-1 involved four repeats. The domain of RAG-1 that associates with SRP1 mapped N-terminal to the zinc finger domain. Because this region of RAG-1 is not required for recombination and SRP1 appears to be bound to the nuclear envelope, we suggest that this interaction helps to localize RAG-1.

176 citations

Journal ArticleDOI
01 Apr 1996-Immunity
TL;DR: Little V kappa J kappa rearrangement could be detected in B cells derived from E kappa NI ES cells, demonstrating that an inserted PGK-neo(r) gene dominantly suppresses V k Kappa J kappas rearrangements.

176 citations

Journal ArticleDOI
TL;DR: The selective accentuation of this protein in A-MuLV transformants and its strong antigenicity in syngeneic animals suggest that it is a unique and functionally important protein.
Abstract: When BALB/c mice were injected with a syngeneic cell line transformed by Abelson murine leukemia virus (A-MuLV), the tumor was usually lethal. In sera from tumor-bearing mice, and at highest levels in sera from mice that reject their tumors, was an antibody that immunoprecipitates a specific protein from [35S]-methionine-labeled A-MuLV-transformed BALB/c cells. This protein was not the previously characterized A-MuLV-specific protein (P120) but a 50,000-molecular-weight protein (P50). Such sera may also immunoprecipitate P120, but no other protein was reproducibly precipitated by them. A monoclonal antibody (RA3-2C2) that has been shown to stain normal B-lymphocytes also selectively immunoprecipitated P50. P50 was present in A-MuLV-transformed lymphoid and fibroblastic cells of a variety of mouse strains. One A-MuLV-transformed cell line had a very low P50 level, the L1-2 tumor of C57L origin. This tumor was previously shown to be rejected by C57L mice and is used to produce anti-P120 (anti-AbT) sera. P50 was not a Moloney MuLV protein and was found at low levels in normal cells of cells transformed by agents other than A-MuLV; thus, it was probably a host cell protein whose concentration was selectively accentuated by A-MuLV transformation. P50 was phosphorylated and, by using indirect immunofluorescence, anti-P50 serum stained live A-MuLV-transformed cells. The protein was not glycosylated and did not label by lactoperoxidase-catalyzed iodination. Thus, P50 was very like P120 in its cellular localization and properties, but it did not exhibit proptein kinase activity in vitro. The selective accentuation of this protein in A-MuLV transformants and its strong antigenicity in syngeneic animals suggest that it is a unique and functionally important protein.

176 citations

Journal ArticleDOI
08 Apr 1988-Cell
TL;DR: It is likely that expression of a single, lymphoid-specific gene in a fibroblast is sufficient to confer V(D)J recombinase activity on that cell.

174 citations


Cited by
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[...]

08 Dec 2001-BMJ
TL;DR: There is, I think, something ethereal about i —the square root of minus one, which seems an odd beast at that time—an intruder hovering on the edge of reality.
Abstract: There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality. Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

33,785 citations

Journal ArticleDOI
15 Feb 2013-Science
TL;DR: The type II prokaryotic CRISPR (clustered regularly interspaced short palindromic repeats)/Cas adaptive immune system has been shown to facilitate RNA-guided site-specific DNA cleavage as discussed by the authors.
Abstract: Functional elucidation of causal genetic variants and elements requires precise genome editing technologies. The type II prokaryotic CRISPR (clustered regularly interspaced short palindromic repeats)/Cas adaptive immune system has been shown to facilitate RNA-guided site-specific DNA cleavage. We engineered two different type II CRISPR/Cas systems and demonstrate that Cas9 nucleases can be directed by short RNAs to induce precise cleavage at endogenous genomic loci in human and mouse cells. Cas9 can also be converted into a nicking enzyme to facilitate homology-directed repair with minimal mutagenic activity. Lastly, multiple guide sequences can be encoded into a single CRISPR array to enable simultaneous editing of several sites within the mammalian genome, demonstrating easy programmability and wide applicability of the RNA-guided nuclease technology.

12,265 citations

Journal ArticleDOI
TL;DR: A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib, and these mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor.
Abstract: BACKGROUND Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown. METHODS We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells. RESULTS Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib. CONCLUSIONS A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib.

10,879 citations

01 Feb 2013
TL;DR: Two different type II CRISPR/Cas systems are engineered and it is demonstrated that Cas9 nucleases can be directed by short RNAs to induce precise cleavage at endogenous genomic loci in human and mouse cells, demonstrating easy programmability and wide applicability of the RNA-guided nuclease technology.
Abstract: Genome Editing Clustered regularly interspaced short palindromic repeats (CRISPR) function as part of an adaptive immune system in a range of prokaryotes: Invading phage and plasmid DNA is targeted for cleavage by complementary CRISPR RNAs (crRNAs) bound to a CRISPR-associated endonuclease (see the Perspective by van der Oost). Cong et al. (p. 819, published online 3 January) and Mali et al. (p. 823, published online 3 January) adapted this defense system to function as a genome editing tool in eukaryotic cells. A bacterial genome defense system is adapted to function as a genome-editing tool in mammalian cells. [Also see Perspective by van der Oost] Functional elucidation of causal genetic variants and elements requires precise genome editing technologies. The type II prokaryotic CRISPR (clustered regularly interspaced short palindromic repeats)/Cas adaptive immune system has been shown to facilitate RNA-guided site-specific DNA cleavage. We engineered two different type II CRISPR/Cas systems and demonstrate that Cas9 nucleases can be directed by short RNAs to induce precise cleavage at endogenous genomic loci in human and mouse cells. Cas9 can also be converted into a nicking enzyme to facilitate homology-directed repair with minimal mutagenic activity. Lastly, multiple guide sequences can be encoded into a single CRISPR array to enable simultaneous editing of several sites within the mammalian genome, demonstrating easy programmability and wide applicability of the RNA-guided nuclease technology.

10,746 citations

Journal ArticleDOI
10 Aug 2001-Science
TL;DR: It is proposed that this epigenetic marking system represents a fundamental regulatory mechanism that has an impact on most, if not all, chromatin-templated processes, with far-reaching consequences for cell fate decisions and both normal and pathological development.
Abstract: Chromatin, the physiological template of all eukaryotic genetic information, is subject to a diverse array of posttranslational modifications that largely impinge on histone amino termini, thereby regulating access to the underlying DNA. Distinct histone amino-terminal modifications can generate synergistic or antagonistic interaction affinities for chromatin-associated proteins, which in turn dictate dynamic transitions between transcriptionally active or transcriptionally silent chromatin states. The combinatorial nature of histone amino-terminal modifications thus reveals a “histone code” that considerably extends the information potential of the genetic code. We propose that this epigenetic marking system represents a fundamental regulatory mechanism that has an impact on most, if not all, chromatin-templated processes, with far-reaching consequences for cell fate decisions and both normal and pathological development.

9,309 citations