About the Lab

Since 2010, LMB has recruited two new investigators, Jinwei Zhang (2015), a biophysicist focusing on the structure and function of non-coding RNAs and Yekaterina Miroshnikova (2021), a cell biologist studying cell responses to mechanochemical signals. The group continued to make seminal discoveries that have long term impact. Key molecular insights were revealed by elucidating a series of important biological complexes: the membrane fission GTPase dynamin (2010, 2011) and an octameric DNA transposase (2014) by Dyda; an outer membrane iron transporter (2012), the Ton motor complex, and the Bam integrase complex (2016) by Buchanan; the V(D)J recombinase Rag1-Rag2 by Yang and Gellert (2015); the human DNA polymerase eta (2010, 2012, 2016) and a phage/bacterial replicasome (2019) by Yang; the HIV intasomes by Craigie (2017 and 2020); and several tRNA-mRNA complexes by Zhang (2019, 2020). Additional key findings include a map of long-range genomic interactions at the insulin locus by Felsenfeld (2014); new protein quality control processes by Ye (2016 and 2020); and the development of an unprecedented in vitro assay that recapitulates DNA partitioning in cells by Mizuuchi (2013).

The 2000s saw a further expansion of LMB, with the addition of Susan Buchanan (2001), Jeremy Berg, Director of NIGMS, (2003), and Yihong Ye (2005). LMB research continued to significantly impact our understanding of molecular mechanisms associated with nucleic acid biology. Craigie discovered the protein BAF, an important cellular factor in the retroviral integration process and, together with Mizuuchi and Krause, first revealed its role in DNA organization (2000); Dyda solved the structure of the first eukaryotic transposase (2005); Felsenfeld demonstrated the differential stability of nucleosomes comprised of variant histones (2007); the structure of an innate immunity Toll receptor protein complexed with double stranded RNA was determined by Davies and Segal (2008); the initial structural insight into RAG1/RAG2 interactions with DNA targets was shown by Gellert and Yang (2009), and the insights into DNA binding affinity and specificity by zinc-finger proteins by Berg (2010), the demonstration of en bloc transfer of polyubiquitin chains to a substrate by Ye (2007), the mechanistic understanding of autotransporter translocation across bacterial membranes by Buchanan in 2007, and the reconstitution and structural understanding of the ESCRT complex in vesicle formation and trafficking by Hurley (2010).

The 1990s were a decade of transition for LMB with a few retirements and some new recruits (Jim Hurley, 1992; Michael Krause, 1993; Wei Yang, 1995; Fred Dyda, 1996). Major contributions from the new investigators included the structure by Hurley of a lipid kinase, insights into the transcriptional regulation of mesodermal cell fate specification by Krause (1998), a structural understanding of DNA mismatch repair by Yang (1998 & 1999), the determination of the first structure of the HIV integrase by Dyda, Craigie, and Davies (1994), the generation of the first functional forms of RAG1 and RAG2 proteins required for V(D)J recombination by Gellert (1995), and the discovery of chromatin insulators and the role of CTCF in enhancer blocking by Felsenfeld (1998,1999).

In the 1980s, Mizuuchi and Robert Craigie expanded the in vitro recombination system to study DNA transposition by bacteriophage Mu (1984), a paradigm later applied to quickly understand HIV integration. An in vitro system for V(D)J recombination, the process by which immunological diversity is generated, was also developed in this period by Gellert and Mizuuchi (1987). This, and related work, made the LMB one of the world centers for the study of recombination mechanisms, a reputation that continues to the present day. Also of note from this decade were a number of key observations including the description of the 30 nm chromatin fiber by Felsenfeld and McGhee (1986), and the structural determination by Davies and Miles of a multi-subunit protein tryptophan synthase (1988).

The ’70s saw a string of LMB discoveries that revolved around nucleic acid dynamics. In the early ’70s, Jun-Ichi Tomizawa, a new addition to LMB, described the first regulatory RNA (1981). Kiyoshi Mizuuchi developed an efficient cell-free system (1976) to study phage lambda integrative recombination. This work set the foundation for a number of groundbreaking discoveries in recombination and other DNA transactions, such as the discovery of DNA gyrase by Mizuuchi and Gellert (1976), and its role as the target of clinically important antibiotics (1977). The role of core histones in chromatin organization was elucidated by Felsenfeld (1976). Another important structural accomplishment was the determination of the immunoglobulin Fab fragment by Davies (1974), the first of several LMB contributions to our understanding of antibody:antigen recognition.

Formed in 1961, the Laboratory of Molecular Biology included Gordon Tomkins, a biochemist; Bruce Ames, a microbial geneticist; David Davies, a structural biologist; Martin Gellert and Gary Felsenfeld, both physical chemists; Todd Miles, an organic chemist; Michael Yarmolinsky, a bacterial geneticist; Terrell Hill, a theoretician; and Harvey Itano, the co-discoverer of sickle cell hemoglobin (HbS). Among some of the early LMB contributions to science were the determination of the structure of chymotrypsin (Davies and Paul Sigler, 1964), the use of micrococcal nuclease to probe chromatin structure (Felsenfeld and Peter Von Hippel, 1964), the discovery by Ames of coordinate repression in the Salmonella histidine operon (1966) and the discovery by Gellert of DNA ligase (1967).