Kevin Struhl Explained

Kevin Struhl (born September 2, 1952) is an American molecular biologist and the David Wesley Gaiser Professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School.[1]   Struhl is primarily known for his work on transcriptional and post transcriptional regulatory mechanisms in yeast using molecular, genetic, biochemical, and genomic approaches.[2]   In addition, he has used related approaches to study transcriptional regulatory circuits involved in cellular transformation and the formation of cancer stem cells.

Kevin Struhl
Birth Date:2 September 1952
Birth Place:Brooklyn, NY
Nationality:American
Alma Mater:Massachusetts Institute of Technology (S.B. and S.M.), Stanford Medical School (Ph.D. 1979)
Fields:Molecular Biology, Cancer
Thesis Title:The yeast his3 gene
Thesis Year:1979
Doctoral Advisor:Ronald W. Davis
Spouse:Marjorie Oettinger (m 1989-2012); 3 children

Early life and education

Kevin Struhl was born on September 2, 1952, in Brooklyn, New York. His father, Joseph Struhl (1921-2008), was an entrepreneur who put up some of the first indoor tennis courts.[3] [4]  His mother, Harriet Schachter Struhl (1927-2024) was a psychologist. He has 3 younger brothers, Gary (1954-), a developmental geneticist at Columbia Medical School, Clifford (1956-) who took over the family business, and Steven (1958-) an orthopedic surgeon.[5]  The Struhl family moved to Great Neck, NY in 1956, where Struhl graduated from Great Neck South high school in 1970. Struhl and his father were once ranked #3 in father-son tennis in the Eastern section of the United States Tennis Association.  Struhl completed his S.B and S.M. in biology in 1974 with Boris Magasanik from the Massachusetts Institute of Technology. He obtained his Ph.D. in 1979 with Ronald W. Davis at Stanford Medical School and then spent two years as a postdoctoral fellow with Sydney Brenner at the Laboratory of Molecular Biology at the Medical Research Council in Cambridge, UK.

Career and Research

Recombinant DNA technology, yeast molecular biology, and reverse genetics

As a graduate student, Struhl cloned and functionally expressed the first eukaryotic protein-coding gene in E.coli, a landmark in recombinant DNA technology.[6] [7] Cloned yeast genes were essential for Gerald Fink to develop transformation methods that Struhl used to co-discover DNA replication origins[8] [9] and to create the first vectors for molecular genetic manipulations in yeast. Struhl was among the first to use “reverse genetic” analysis; i.e., making mutations in cloned genes, introducing the mutated derivatives back into cells, and assessing the resulting phenotypes.

Structure and function of eukaryotic promoters: the yeast his3 paradigm

Using “reverse genetics” to study gene regulation in vivo, Struhl generated the first eukaryotic promoter mutants and performed a detailed analysis of the his3 gene. This resulted in early descriptions of all the basic types of gene-regulatory elements: upstream elements that act a distance from the promoter;[10] [11] regulatory sites that activate gene expression in specific conditions;[12] poly(dA:dT) sequences;[13] functionally distinct TATA elements;[14] [15] initiator elements;[16] repression sequences that act upstream of and at a distance from promoters.[17]

Structure and function of a transcriptional activator, the yeast Gcn4 paradigm

Struhl invented “reverse biochemistry”, the use of in vitro synthesized proteins to identify DNA-binding transcription factors and study protein-DNA interactions.[18]  In one of the first examples of a eukaryotic sequence-specific binding protein, he discovered that Gcn4 coordinately activates many genes involved in amino acid biosynthesis by direct binding to target sites in their promoters. He developed the first “random selection” method for selecting DNA target sites (and other genetic elements) from random-sequence oligonucleotides.[19] He showed that Gcn4 binds as a dimer[20] via its leucine zipper,[21] described how it recognizes target sites at atomic resolution,[22] and showed that the Gcn4 binding surface folds when bound to its target site, the first example of an “induced fit” model for DNA binding.[23] Detailed genetic dissection led to the discovery of short acidic activation domains required for transcription that are functionally autonomous and can be encoded by different sequences.[24] [25]  Lastly, Struhl showed that the Jun oncogene encodes a Gcn4 homolog that binds the same sequences[26] and activates transcription in yeast cells.[27]  Jun was the first example of an oncogene that encodes a transcription factor.

Transcriptional regulatory mechanisms

Using T7 RNA polymerase in yeast cells, Struhl demonstrated distinct chromatin-accessibility and protein-protein interaction mechanisms for transcriptional activation.[28]  Novel genetic approaches - altered-specificity mutants,[29] protein fusions for artificial recruitment[30] [31] - along with chromatin immunoprecipitation (ChIP), demonstrated that transcriptional regulation in yeast occurs primarily at the level of recruitment of the RNA polymerase II transcription machinery.[32] Struhl showed that the TATA-binding protein is required for transcription by all 3 nuclear RNA polymerases[33] and defined a surface required specifically for transcription by RNA polymerase III.[34]  Together with Tom Gingeras, he used tiled microarrays to generate the first unbiased, genome-scale analysis of transcription factor binding in mammalian cells, leading to the discovery of far more transcription binding sites in vivo than predicted, including many that control non-coding RNAs.[35] [36]   His contributions in diverse areas of transcriptional regulation include mechanistic roles of general factors for transcriptional initiation,[37] [38] [39] [40] promoter directionality,[41] high level of transcriptional noise due to infidelity of Pol II initiation,[42] role of TAFs[43] [44] [45] and Mediator[46] [47] in transcriptional activation, coordinate regulation of ribosomal protein genes in response to growth and stress signals,[48] [49] repression by the Cyc8-Tup co-repressor complex that controls numerous stress pathways,[50] [51] the response to osmotic stress[52] including the discovery of a pre-transcriptional response,[53] transcriptional elongation,[54] [55] 3’ end formation,[56] and mRNA stability.[57] [58]  Lastly, Struhl was among the first to use ChIP to analyze transcription in E. coli, showing that the transition between initiation and elongation is highly variable and often rate-limiting[59] and uncovering extensive functional overlap between sigma factors.[60]

Role of chromatin in transcription and DNA replication

Struhl’s work on the role of chromatin in transcriptional regulation include initial descriptions of 1) a DNA sequence, poly(dA:dT), that activates transcription via its intrinsic effect on nucleosome stability,[61] [62] 2) mechanistic principles for how the nucleosome positioning pattern occurs in vivo,[63] [64] 3) transcriptional repression via targeted recruitment of a histone deacetylase,[65] [66] 4) molecular memory of recent transcriptional activity via targeted histone methylation via recruitment by elongating Pol II,[67] 5) dynamic eviction and re-association of histones during transcriptional elongation,[68] and 6) methylation of lysine 79 within the histone H3 core[69] and a model for position-effect variegation.[70]  With respect to DNA replication, Struhl demonstrated that a histone acetylase (HBO1) is both a transcriptional co-activator and a co-activator for the Cdt1 replication licensing factor[71] [72] that coordinates the transcriptional and DNA replication response to non-genotoxic stress.[73]  In addition, he showed that the DNA origin replication complex (ORC) selectively binds regions with a specific chromatin pattern, and that the location of ORC binding sites plays a major role in DNA replication timing.[74]

An epigenetic switch linking inflammation to cancer

Struhl discovered an epigenetic switch from non-transformed to transformed cells, a new type of step in cancer progression distinct from mutation or DNA methylation.[75]  This epigenetic switch is mediated by a positive inflammatory feedback loop that involves the joint role of the NF-kB, STAT3, AP-1, and TEAD transcription factors along with YAP/TAZ co-activators as well as Let7 and other microRNAs.[76] [77] [78]  He also uncovered a dynamic equilibrium between cancer stem cells and non-stem cancer cells mediated by interleukin 6[79] and defined the transcriptional circuit mediating the biphasic switch between these physiological states.[80] [81]

Anti-cancer and anti-inflammatory properties of metformin

Struhl showed that metformin, the first-line drug for treating type 2 diabetes, selectively kills cancer stem cells and acts together with chemotherapy to inhibit tumor progression and prolong remission.[82] [83]  Metformin exerts its effects on cellular transformation and cancer stem cell growth via its inhibitory effect on the inflammatory pathway.[84]

Awards

Notes and References

  1. Web site: Chandler . Courtney . 2022-12-02 . 'Independent agents' no more . American Society for Biochemistry and Molecular Biology.
  2. Struhl . Kevin . Yeast Transcriptional Regulatory Mechanisms . 1995 . Annual Review of Genetics. 29 . 651–674 . 10.1146/annurev.ge.29.120195.003251 . 8825489 .
  3. Horn . Houston . 1965-03-08 . As Long As There's A Place To Go, Let It Snow . Sports Illustrated .
  4. News: Friedman . Charles . 1964-11-22 . $400,000 Indoor Tennis Center With 4 Clay Courts Opens Here . The New York Times .
  5. Web site: Dr. Steven Struhl NYC Orthopedic Surgeon . Shoulders & Knees Steven Struhl MD.
  6. Struhl . K . Davis . RW . 1977-12-01 . Production of a functional eukaryotic enzyme in Escherichia coli: cloning and expression of the yeast structural gene for imidazole-glycerolphosphate dehydratase (his3) . PNAS. 74 . 12 . 5255–5259 . 10.1073/pnas.74.12.5255 . 341150 . 431671 . 1977PNAS...74.5255S . free .
  7. Struhl . K . Cameron . JR . Davis . RW . 1976-05-01 . Functional genetic expression of eukaryotic DNA in Escherichia coli. . PNAS. 73 . 5 . 1471–1475 . 10.1073/pnas.73.5.1471 . 775490 . 430318 . 1976PNAS...73.1471S . free .
  8. Struhl . K . Stinchcomb . DT . Scherer . S . Davis . RW . 1979-03-01 . High-frequency transformation of yeast: autonomous replication of hybrid DNA molecules . PNAS. 76 . 3 . 1035–1039 . 10.1073/pnas.76.3.1035 . 375221 . 383183 . 1979PNAS...76.1035S . free .
  9. Stinchcomb . DT . Struhl . K . Davis . RW . 1979-11-01 . Isolation and characterization of a yeast chromosomal replicator . Nature. 282 . 5734 . 39–43 . 10.1038/282039a0 . 388229 . 1979Natur.282...39S . 4326901 .
  10. Struhl . Kevin . 1981-07-01 . Deletion mapping a eukaryotic promoter . PNAS. 78 . 7 . 4461–4465 . 10.1073/pnas.78.7.4461 . 7027262 . 319811 . 1981PNAS...78.4461S . free .
  11. Struhl . Kevin . 1979 . The yeast his3 gene . Biochemistry.
  12. Struhl . Kevin . 1982-11-18 . Regulatory sites for his3 expression in yeast . Nature. 300 . 5889 . 285–286 . 10.1038/300284a0 . 6755264 . 4308484 .
  13. Struhl . Kevin . 1985-12-01 . Naturally occurring poly(dA-dT) sequences are upstream promoter elements for constitutive transcription in yeast . PNAS. 82 . 24 . 8419–8423 . 10.1073/pnas.82.24.8419 . 3909145 . 390927 . 1985PNAS...82.8419S . free .
  14. Chen . W . Struhl . K . 1988-04-01 . Saturation mutagenesis of a yeast his3 TATA element: genetic evidence for a specific TATA-binding protein . PNAS. 85 . 8 . 2691–2695 . 10.1073/pnas.85.8.2691 . 3282236 . 280064 . 1988PNAS...85.2691C . free .
  15. Struhl . Kevin . 1986-05-29 . Constitutive and inducible Saccharomyces cerevisiae promoters: evidence for two distinct molecular mechanisms . Molecular and Cellular Biology. 6 . 11 . 3847–3853 . 10.1128/mcb.6.11.3847-3853.1986 . 3540601 . 367147 .
  16. Chen . W . Struhl . K . 1985-12-01 . Yeast mRNA initiation sites are determined primarily by specific sequences, not by the distance from the TATA element . The EMBO Journal. 4 . 12 . 3273–3280 . 10.1002/j.1460-2075.1985.tb04077.x . 3912167 . 554654 .
  17. Struhl . Kevin . 1985-10-01 . Negative control at a distance mediates catabolite repression in yeast . Nature. 317 . 6040 . 822–824 . 10.1038/317822a0 . 3903516 . 1985Natur.317..822S . 2404872 .
  18. Hope . IA . Struhl . K . November 1988 . GCN4 protein, synthesized in vitro, binds to HIS3 regulatory sequences: implications for the general control of amino acid biosynthetic genes in yeast . Cell. 43 . 1 . 177–188 . 10.1016/0092-8674(85)90022-4 . 3907851 . 22627291 .
  19. Oliphant . AR . Brandl . CJ . Struhl . K . 1989-07-01 . Defining sequence specificity of DNA-binding proteins by selecting binding sites from random-sequence oligonucleotides: Analysis of the yeast GCN4 protein . Molecular and Cellular Biology. 9 . 7 . 2944–2949 . 10.1128/mcb.9.7.2944-2949.1989 . 2674675 . 362762 .
  20. Hope . IA . Struhl . K . 1987-09-01 . GCN4, a eukaryotic transcriptional activator protein, binds as a dimer to target DNA . The EMBO Journal. 6 . 9 . 2781–2784 . 10.1002/j.1460-2075.1987.tb02573.x . 3678204 . 553703 .
  21. Sellers . JW . Struhl . K . 1989-09-07 . Changing fos oncoprotein to a DNA-binding protein with GCN4 dimerization specificity by swapping "leucine zippers" . Nature. 341 . 6237 . 74–76 . 10.1038/341074a0 . 2505087 . 4253004 .
  22. Ellenberger . Thomas E . Brandl . Christopher J . Struhl . Kevin . Harrison . Stephen C . 1992-12-24 . The GCN4 basic-region-leucine zipper binds DNA as a dimer of uninterrupted a-helices: crystal structure of the protein-DNA complex . Cell. 71 . 7 . 1223–1237 . 10.1016/S0092-8674(05)80070-4 . 1473154 . 13548424 .
  23. Weiss . Michael A . Ellenberger . Thomas . Wobbe . C Richard . Lee . Jonathan P . Harrison . Stephen C . Struhl . Kevin . Folding transition in the DNA-binding domain of GCN4 on specific binding to DNA . Nature. 1990 . 347 . 6293 . 575–578 . 10.1038/347575a0 . 2145515 . 1990Natur.347..575W . 4366430 .
  24. Hope . IA . Struhl . K . 1986-09-12 . Functional dissection of a eukaryotic transcriptional activator protein, GCN4 of yeast . Cell. 46 . 6 . 885–894 . 10.1016/0092-8674(86)90070-X . 3530496 . 40730692 .
  25. Hope . IA . Mahadevan . S . Struhl . K . 1988-06-16 . Structural and functional characterization of the short acidic transcriptional activation region of yeast GCN4 protein . Nature. 333 . 6174 . 635–640 . 10.1038/333635a0 . 3287180 . 1988Natur.333..635H . 2635634 .
  26. Struhl . Kevin . 1987-09-11 . The DNA-binding domains of the jun oncoprotein and the yeast GCN4 transcriptional activator are functionally homologous . Cell. 50 . 6 . 841–846 . 10.1016/0092-8674(87)90511-3 . 3040261 . 29588878 .
  27. Struhl . Kevin . 1988-04-14 . The JUN oncoprotein, a vertebrate transcription factor, activates transcription in yeast . Nature. 332 . 6165 . 649–650 . 10.1038/332649a0 . 3128739 . 1988Natur.332..649S . 4350206 .
  28. Chen . W . Tabor . S . Struhl . K . 1987-09-25 . Distinguishing between mechanisms of eukaryotic transcriptional activation with bacteriophage T7 RNA polymerase . Cell. 266 . 5183 . 280–282 . 10.1126/science.7939664 . 7939664 .
  29. Klein . C . Struhl . K . 1994-10-19 . Increased recruitment of TATA-binding protein to the promoter by transcriptional activation domains in vivo . Science. 266 . 5183 . 280–282 . 10.1126/science.7939664 . 7939664 .
  30. Keaveney . M . Struhl . K . May 1998 . Activator-mediated recruitment of the RNA polymerase II machinery is the predominant mechanism for transcriptional activation in yeast . Molecular Cell. 1 . 6 . 917–924 . 10.1016/S1097-2765(00)80091-X . 9660975 . free .
  31. Chatterjee . S . Struhl . K . 1995-04-27 . Connecting a promoter-bound protein to TBP bypasses the need for a transcriptional activation domain . Nature. 374 . 6525 . 820–822 . 10.1038/374820a0 . 7723828 . 4325887 .
  32. Kuras . L . Struhl . K . 1999-06-10 . Binding of TBP to promoters in vivo is stimulated by activators and requires Pol II holoenzyme . Nature. 399 . 6736 . 609–613 . 10.1038/21239 . 10376605 . 204993837 .
  33. Cormack . BP . Struhl . K . 1992-05-15 . The TATA-binding protein is required for transcription by all three nuclear RNA polymerases in yeast cells . Cell. 69 . 4 . 685–696 . 10.1016/0092-8674(92)90232-2 . 1586947 . 7419671 .
  34. Cormack . BP . Struhl . K . 1993-10-08 . Regional codon randomization: defining a TATA-binding protein surface required for RNA polymerase III transcription . Science. 262 . 5131 . 244–248 . 10.1126/science.8211143 . 8211143 .
  35. Cawley . S. . et al . 2004-02-20 . Unbiased mapping of transcription factor binding sites along human chromosomes 21 and 22 points to widespread regulation of non-coding RNAs . Cell. 116 . 4 . 499–509 . 10.1016/S0092-8674(04)00127-8 . 14980218 . 7793221 . free .
  36. Yang . Annie . Zhu . Zhou . Kapranov . Philipp . McKeon . Frank . Church . George M . Gingeras . Thomas R . Struhl . Kevin . 2006-11-17 . Relationships between p63 binding, DNA sequence, transcription activity, and biological function in human cells . Molecular Cell. 24 . 4 . 593–602 . 10.1016/j.molcel.2006.10.018 . 17188034 . free .
  37. Stargell . LA . Struhl . K . 1995-07-07 . The TBP-TFIIA interaction in the response to acidic activators in vivo . Science. 269 . 5220 . 75–78 . 10.1126/science.7604282 . 7604282 .
  38. Lee . M . Struhl . K . 1995-07-11 . Mutations on the DNA-binding surface of TATA-binding protein can specifically impair the response to acidic activators in vivo . Molecular and Cellular Biology. 15 . 10 . 5461–5469 . 10.1128/MCB.15.10.5461 . 7565697 . 230796 .
  39. Petrenko . Natalia . Yi . Jin . Dong . Liguo . Wong . Koon Ho . Struhl . Kevin . 2019-01-25 . Requirements for RNA polymerase II preinitiation complex formation in vivo . eLife. 8 . 10.7554/eLife.43654.023 . 30681409 . 6366898 . free .
  40. Wong . Koon Ho . Yi . Jin . Struhl . Kevin . 2014-05-22 . TFIIH phosphorylation of the Pol II CTD stimulates Mediator dissociation from the preinitiation complex and promoter escape . Molecular Cell. 54 . 4 . 601–612 . 10.1016/j.molcel.2014.03.024 . 24746699 . 4035452 .
  41. Yi . Jin . Eser . Umut . Struhl . Kevin . Churchman . L Stirling . 2017-08-24 . The ground state and evolution of promoter regions directionality . Cell. 170 . 5 . 889–898.e10 . 10.1016/j.cell.2017.07.006 . 28803729 . 5576552 .
  42. Struhl . Kevin . February 2007 . Transcriptional noise and the fidelity of initiation by RNA polymerase II . Nature Structural & Molecular Biology . 14 . 2 . 103–105. 10.1038/nsmb0207-103 . 17277804 . 29398526 .
  43. Moqtaderi . Zarmik . Bai . Yu . Poon . David . Weil . P Anthony . Struhl . Kevin . 1996-09-12 . TBP-associated factors are not generally required for transcriptional activation in yeast . Nature. 383 . 6596 . 188–191 . 10.1038/383188a0 . 8774887 . 4351320 .
  44. Kuras . Laurent . Kosa . Peter . Mencia . Mario . Struhl . Kevin . 2000-05-19 . TAF-containing and TAF-independent forms of transcriptionally active TBP in vivo . Science . 288 . 5469 . 1244–1248. 10.1126/science.288.5469.1244 . 10818000 .
  45. Mencia . Mario . Moqtaderi . Zarmik . Geisberg . Joseph V . Kuras . Laurent . Struhl . Kevin . April 2002 . Activator-specific recruitment of TFIID and regulation of ribosomal protein genes in yeast . Molecular Cell . 9 . 4 . 823–833. 10.1016/S1097-2765(02)00490-2 . 11983173 . free .
  46. Fan . Xiaochun . Chou . Danny M . Struhl . Kevin . 2006-01-22 . Activator-specific recruitment of Mediator in vivo . Nature Structural & Molecular Biology. 13 . 2 . 117–120 . 10.1038/nsmb1049 . 16429153 . 20626638 .
  47. Petrenko . Natalia . Jin . Yi . Wong . Koon Ho . Struhl . Kevin . 2016-11-03 . Mediator Undergoes a Compositional Change during Transcriptional Activation . Molecular Cell. 64 . 3 . 443–454 . 10.1016/j.molcel.2016.09.015 . 27773675 . 5096951 .
  48. Klein . C . Struhl . K . March 1994 . Protein kinase A mediates growth-regulated expression of yeast ribosomal protein genes by modulating RAP1 transcriptional activity . Molecular and Cellular Biology . 14 . 3 . 1920–1928. 10.1128/mcb.14.3.1920-1928.1994 . 8114723 . 358550 .
  49. Wade . Joseph T . Hall . Daniel B . Struhl . Kevin . 2004-12-23 . The transcription factor Ifh1 is a key regulator of yeast ribosomal protein genes . Nature. 432 . 7020 . 1054–1058 . 10.1038/nature03175 . 15616568 . 4334147 .
  50. Tzamarias . D . Struhl . K . 1994-06-30 . Functional dissection of the yeast Cyc8-Tup1 transcriptional corepressor complex . Nature. 369 . 6483 . 758–761 . 10.1038/369758a0 . 8008070 . 4304771 .
  51. Wong . Koon Ho . Struhl . Kevin . 2011-12-01 . The Cyc8-Tup1 complex inhibits transcription primarily by masking the activation domain of the recruiting protein . Genes & Development . 25 . 23 . 2525–2539. 10.1101/gad.179275.111 . 22156212 . 3243062 .
  52. Proft . M . Struhl . K . June 2002 . Hog1 kinase converts the Sko1-Cyc8-Tup1 repressor complex into an activator that recruits SAGA and SWI/SNF in response to osmotic stress . Molecular Cell . 9 . 6 . 1307–1317. 10.1016/S1097-2765(02)00557-9 . 12086627 . free .
  53. Proft . M . Struhl . K . 2004-08-06 . A MAP kinase-mediated stress relief response that precedes and regulates the timing of transcriptional induction . Cell. 118 . 3 . 351–361 . 10.1016/j.cell.2004.07.016 . 15294160 . 2022911 . free .
  54. Mason . Paul B . Struhl . Kevin . 2005-03-18 . Distinction and relationship between elongation rate and processivity of RNA polymerase II in vivo . Molecular Cell. 17 . 6 . 831–840 . 10.1016/j.molcel.2005.02.017 . 15780939 . free .
  55. Geisberg . Joseph V . Moqtaderi . Zarmik . Struhl . Kevin . 2020-08-26 . The transcriptional elongation rate regulates alternative polyadenylation in yeast . eLife. 9 . 10.7554/eLife.59810.sa2 . 32845240 . 7532003 . free .
  56. Geisberg . Joseph V . Moqtaderi . Zarmik . Fong . Nova . Erickson . Benjamin . Bentley . David L . Struhl . Kevin . 2022-11-24 . Nucleotide-level linkage of transcriptional elongation and polyadenylation . eLife. 11 . 10.7554/eLife.83153.sa2 . 36421680 . 9721619 . free .
  57. Geisberg . Joseph V . Moqtaderi . Zarmik . Fan . Xiaochun . Ozsolak . Fatih . Struhl . Kevin . 2014-02-13 . Global analysis of mRNA isoform half-lives reveals stabilizing and destabilizing elements in yeast . Cell. 156 . 4 . 812–824 . 10.1016/j.cell.2013.12.026 . 24529382 . 3939777 .
  58. Moqtaderi . Zarmik . Geisberg . Joseph V . Struhl . Kevin . October 2018 . Extensive structural differences of closely related 3' mRNA isoforms: links to Pab1 binding and mRNA stability . Molecular Cell. 72 . 5 . 849–861.e6 . 10.1016/j.molcel.2018.08.044 . 30318446 . 6289678 .
  59. Reppas . Nikos B . Wade . Joseph T . Church . George M . Struhl . Kevin . 2006-12-08 . The transition between transcriptional initiation and elongation in E. coli is highly variable and often rate-limiting . Molecular Cell. 24 . 5 . 747–757 . 10.1016/j.molcel.2006.10.030 . 17157257 . free .
  60. Wade . Joseph T . Roa . Daniel Castro . Grainger . David C . Hurd . Douglas . Busby . Stephen JW . Struhl . Kevin . Nudler . Evgeny . 2006-08-06 . Extensive functional overlap between σ factors in Escherichia coli . Nature Structural & Molecular Biology. 13 . 9 . 806–814 . 10.1038/nsmb1130 . 16892065 . 19816595 .
  61. Iyer . V . Struhl . K . June 1995 . Poly(dA:dT), a ubiquitous promoter element that stimulates transcription via its intrinsic structure . The EMBO Journal. 14 . 11 . 2570–2579. 10.1002/j.1460-2075.1995.tb07255.x . 7781610 . 398371 .
  62. Sekinger . Edward A . Moqtaderi . Zarmik . Struhl . Kevin . 2005-06-10 . Intrinsic histone-DNA interactions and low nucleosome density are important for preferential accessibility of promoter regions in yeast . Molecular Cell . 18 . 6 . 735–748. 10.1016/j.molcel.2005.05.003 . 15949447 . free .
  63. Zhang . Yong . Moqtaderi . Zarmik . Rattner . Barbara P . Euskirchen . Ghia . Snyder . Michael . Kadonaga . James T . Liu . X Shirley . Struhl . Kevin . 2009-07-20 . Intrinsic histone-DNA interactions are not the major determinant of nucleosome positions in vivo . Nature Structural & Molecular Biology . 16 . 8 . 847–852. 10.1038/nsmb.1636 . 19620965 . 2823114 . 11805076 .
  64. Hughes . Amanda L . Jin . Yi . Rando . Oliver J . Struhl . Kevin . 2012-10-12 . A Functional Evolutionary Approach to Identify Determinants of Nucleosome Positioning: A Unifying Model for Establishing the Genome-wide Pattern . Molecular Cell . 48 . 1 . 5–15. 10.1016/j.molcel.2012.07.003 . 22885008 . 3472102 .
  65. Kadosh . David . Struhl . Kevin . 1997-05-02 . Repression by Ume6 Involves Recruitment of a Complex Containing Sin3 Corepressor and Rpd3 Histone Deacetylase to Target Promoters . Cell . 89 . 3 . 365–371. 10.1016/S0092-8674(00)80217-2 . 9150136 . 15115179 . free .
  66. Kadosh . David . Struhl . Kevin . September 1998 . Targeted Recruitment of the Sin3-Rpd3 Histone Deacetylase Complex Generates a Highly Localized Domain of Repressed Chromatin In Vivo . Molecular and Cellular Biology . 18 . 9 . 5121–5127. 10.1128/MCB.18.9.5121 . 9710596 . 109097 .
  67. Ng . Huck Hui . Robert . Francois . Young . Richard A . Struhl . Kevin . March 2003 . Targeted Recruitment of Set1 Histone Methylase by Elongating Pol II Provides a Localized Mark and Memory of Recent Transcriptional Activity . Molecular Cell . 11 . 3 . 709–719. 10.1016/S1097-2765(03)00092-3 . 12667453 . free .
  68. Schwabish . Marc A . Struhl . Kevin . December 2004 . Evidence for Eviction and Rapid Deposition of Histones upon Transcriptional Elongation by RNA Polymerase II . Molecular and Cellular Biology . 24 . 23 . 10111–10117. 10.1128/MCB.24.23.10111-10117.2004 . 15542822 . 529037 .
  69. Ng . Huck Hui . Feng . Qin . Wang . Hengbin . Erdjument-Bromage . Hediye . Tempst . Paul . Zhang . Yi . Struhl . Kevin . 2002 . Lysine methylation within the globular domain of histone H3 by Dot1 is important for telomeric silencing and Sir protein association . Genes & Development . 16 . 12 . 1518–1527. 10.1101/gad.1001502 . 12080090 . 186335 .
  70. Ng . Huck Hui . Ciccone . David N . Morshead . Katrina B . Oettinger . Marjorie A . Struhl . Kevin . 2003-02-06 . Lysine-79 of histone H3 is hypomethylated at silenced loci in yeast and mammalian cells: A potential mechanism for position-effect variegation . PNAS . 100 . 4 . 1820–1825. 10.1073/pnas.0437846100 . 12574507 . 149917 . free .
  71. Miotto . Benoit . Struhl . Kevin . 2008 . HBO1 histone acetylase is a coactivator of the replication licensing factor Cdt1 . Genes & Development . 22 . 19 . 2633–2638. 10.1101/gad.1674108 . 18832067 . 2559906 .
  72. Miotto . Benoit . Struhl . Kevin . 2010-01-15 . HBO1 Histone Acetylase Activity Is Essential for DNA Replication Licensing and Inhibited by Geminin . Molecular Cell . 37 . 1 . 57–66. 10.1016/j.molcel.2009.12.012 . 20129055 . 2818871 .
  73. Miotto . Benoit . Struhl . Kevin . 2011-10-07 . JNK1 Phosphorylation of Cdt1 Inhibits Recruitment of HBO1 Histone Acetylase and Blocks Replication Licensing in Response to Stress . Molecular Cell . 44 . 1 . 62–71. 10.1016/j.molcel.2011.06.021 . 21856198 . 3190045 .
  74. Miotto . Benoit . Ji . Zhe . Struhl . Kevin . 2016-06-14 . Selectivity of ORC binding sites and the relation to replication timing, fragile sites, and deletions in cancers . PNAS . 113 . 33 . 4810–4819. 10.1073/pnas.1609060113 . 27436900 . 4995967 . free .
  75. Iliopoulos . Dimitrios . Hirsch . Heather A . Struhl . Kevin . 2009-11-13 . An Epigenetic Switch Involving NF-κB, Lin28, Let-7 MicroRNA, and IL6 Links Inflammation to Cell Transformation . Cell . 139 . 4 . 693–706. 10.1016/j.cell.2009.10.014 . 19878981 . 2783826 .
  76. He . Lizhi . Pratt . Henry . Gao . Mingshi . Wei . Fengxiang . Weng . Zhiping . Struhl . Kevin . 2021-08-21 . YAP and TAZ are transcriptional co-activators of AP-1 proteins and STAT3 during breast cellular transformation . eLife. 10 . 10.7554/eLife.67312 . 34463254 . 8463077 . free .
  77. Iliopoulos . Dimitrios . Jaeger . Savina A . Hirsch . Heather A . Bulyk . Martha L . Struhl . Kevin . 2010-08-27 . STAT3 Activation of miR-21 and miR-181b-1 via PTEN and CYLD Are Part of the Epigenetic Switch Linking Inflammation to Cancer . Molecular Cell . 39 . 4 . 493–506. 10.1016/j.molcel.2010.07.023 . 20797623 . 2929389 .
  78. Ji . Zhe . He . Lizhi . Regev . Aviv . Struhl . Kevin . 2019-03-25 . Inflammatory regulatory network mediated by the joint action of NF-kB, STAT3, and AP-1 factors is involved in many human cancers . PNAS . 116 . 19 . 9453–9462. 10.1073/pnas.1821068116 . 30910960 . 6511065 . free .
  79. Iliopoulos . Dimitrios . Hirsch . Heather A . Wang . Guannan . Struhl . Kevin . 2011-01-10 . Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion . PNAS . 108 . 4 . 1397–1402. 10.1073/pnas.1018898108 . 21220315 . 3029760 . free .
  80. Iliopoulos . Dimitrios . Lindahl-Allen . Marianne . Polytarchou . Christos . Hirsch . Heather A . Tsichlis . Philip N . Struhl . Kevin . 2010-09-10 . Loss of miR-200 Inhibition of Suz12 Leads to Polycomb-Mediated Repression Required for the Formation and Maintenance of Cancer Stem Cells . Molecular Cell . 39 . 5 . 761–772. 10.1016/j.molcel.2010.08.013 . 20832727 . 2938080 .
  81. Polytarchou . Christos . Iliopoulos . Dimitrios . Struhl . Kevin . 2012-08-20 . An integrated transcriptional regulatory circuit that reinforces the breast cancer stem cell state . PNAS . 109 . 36 . 14470–14475. 10.1073/pnas.1212811109 . 22908280 . 3437881 . free .
  82. Hirsch . Heather A . Iliopoulos . Dimitrios . Tsichlis . Philip N . Struhl . Kevin . 2009-10-01 . Metformin Selectively Targets Cancer Stem Cells, and Acts Together with Chemotherapy to Block Tumor Growth and Prolong Remission . Cancer Research . 69 . 19 . 7507–7511. 10.1158/0008-5472.CAN-09-2994 . 19752085 . 2756324 .
  83. Iliopoulos . Dimitrios . Hirsch . Heather A . Struhl . Kevin . 2011-04-29 . Metformin Decreases the Dose of Chemotherapy for Prolonging Tumor Remission in Mouse Xenografts Involving Multiple Cancer Cell Types . Cancer Research . 71 . 9 . 3196–3201. 10.1158/0008-5472.CAN-10-3471 . 21415163 . 3085572 .
  84. Hirsch . Heather A . Iliopoulos . Dimitrios . Struhl . Kevin . 2012-12-31 . Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth . PNAS . 110 . 3 . 972–977. 10.1073/pnas.1221055110 . 23277563 . 3549132 . free .
  85. Web site: American Academy of Arts & Sciences . American Academy of Arts & Sciences. 12 July 2023 .
  86. Web site: 2014 . National Academy of Sciences . National Academy of Sciences.
  87. Web site: 2015 . National Academy of Medicine . National Academy of Medicine.
  88. Web site: 2018-09-13 . Who's Who Lifetime Achievement . Who's Who Lifetime Achievement.
  89. Web site: December 7, 2023 . YouTube - Stanford Medicine Alumni Association .
  90. Web site: Stanford University Alumni Association . Stanford Medicine.

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