About

Max E. Gottesman, PhD, is the Charles H. Revson Professor of Biochemistry and Molecular Biophysics and Microbiology at Columbia University, within the Institute of Cancer Research. His research focuses on the hormonal regulation of gene expression, the phage HK022 Nun transcription termination protein, and the regulation of transcription termination in both Escherichia coli and bacteriophage. Additionally, his work encompasses the repair of DNA damage in prokaryotes and eukaryotes. Through these research interests, Professor Gottesman contributes to a deeper understanding of fundamental molecular processes that govern gene expression and genome maintenance across different biological systems.

Research topics

• Cell biology
• Biology
• Computational biology
• Genetics
• Neuroscience
• Pathology
• Chemistry
• Biophysics
• Biochemistry

Selected publications

• Single-molecule tracking reveals the functional allocation, in vivo interactions, and spatial organization of universal transcription factor NusG

  Molecular Cell · 2024-02-21 · 25 citations

  articleOpen access

  During transcription elongation, NusG aids RNA polymerase by inhibiting pausing, promoting anti-termination on rRNA operons, coupling transcription with translation on mRNA genes, and facilitating Rho-dependent termination. Despite extensive work, the in vivo functional allocation and spatial distribution of NusG remain unknown. Using single-molecule tracking and super-resolution imaging in live E. coli cells, we found NusG predominantly in a chromosome-associated population (binding to RNA polymerase in elongation complexes) and a slowly diffusing population complexed with the 30S ribosomal subunit; the latter provides a "30S-guided" path for NusG into transcription elongation. Only ∼10% of NusG is fast diffusing, with its mobility suggesting non-specific interactions with DNA for >50% of the time. Antibiotic treatments and deletion mutants revealed that chromosome-associated NusG participates mainly in rrn anti-termination within phase-separated transcriptional condensates and in transcription-translation coupling. This study illuminates the multiple roles of NusG and offers a guide on dissecting multi-functional machines via in vivo imaging.

  PublisherDOI

• How Dedicated Ribosomes Translate a Leaderless mRNA

  Journal of Molecular Biology · 2024-01-05 · 3 citations

  articleOpen accessCorresponding
  PublisherOA PDFDOI

• Structural insight into translation initiation of the <i>λ</i> cl leaderless mRNA

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-09-02

  preprintOpen accessCorresponding

  Abstract In bacteriophage λ lysogens, the λ cI repressor is encoded by the leaderless transcript (lmRNA) initiated at the λ pRM promoter. Translation is enhanced in rpsB mutants deficient in ribosomal protein uS2. Although translation initiation of lmRNA is conserved in bacteria, archaea, and eukaryotes, structural insight of a lmRNA translation initiation complex is missing. Here, we use cryo-EM to solve the structures of the uS2-deficient 70S ribosome of host E. coli mutant rpsB11 and the wild-type 70S complex with λ cI lmRNA and fmet-tRNA fMet . Importantly, the uS2-deficient 70S ribosome also lacks protein bS21. The anti-Shine-Dalgarno (aSD) region is structurally supported by bS21, so that the absence of the latter causes the aSD to divert from the normal mRNA exit pathway, easing the exit of lmRNA. A π-stacking interaction between the monitor base A1493 and A(+4) of lmRNA potentially acts as a recognition signal. Coulomb charge flow, along with peristalsis-like dynamics within the mRNA entry channel due to the increased 30S head rotation caused by the absence of uS2, are likely to facilitate the propagation of lmRNA through the ribosome. These findings lay the groundwork for future research on the mechanism of translation and the co-evolution of lmRNA and mRNA that includes the emergence of a defined ribosome-binding site of the transcript.

  PublisherOA PDFDOI

• Author Correction: Multiscale reorganization of the genome following DNA damage facilitates chromosome translocations via nuclear actin polymerization

  Nature Structural & Molecular Biology · 2023-04-14 · 2 citations

  erratumOpen access
  PublisherOA PDFDOI

• Mechanisms of insertions at a DNA double-strand break

  Molecular Cell · 2023-07-01 · 24 citations

  articleOpen access
  PublisherOA PDFDOI

• Non-cell-autonomous disruption of nuclear architecture as a potential cause of COVID-19-induced anosmia

  Cell · 2022 · 267 citations

  • Biology
  • Neuroscience
  • Cell biology
  PublisherOA PDFDOI

• Multiscale reorganization of the genome following DNA damage facilitates chromosome translocations via nuclear actin polymerization

  Nature Structural & Molecular Biology · 2022 · 71 citations

  • Biology
  • Cell biology
  • Computational biology

  Nuclear actin-based movements have been shown to orchestrate clustering of DNA double-strand breaks (DSBs) into homology-directed repair domains. Here we describe multiscale three-dimensional genome reorganization following DNA damage and analyze the contribution of the nuclear WASP-ARP2/3-actin pathway toward chromatin topology alterations and pathologic repair. Hi-C analysis reveals genome-wide, DNA damage-induced chromatin compartment flips facilitated by ARP2/3 that enrich for open, A compartments. Damage promotes interactions between DSBs, which in turn facilitate aberrant, actin-dependent intra- and inter-chromosomal rearrangements. Our work establishes that clustering of resected DSBs into repair domains by nuclear actin assembly is coordinated with multiscale alterations in genome architecture that enable homology-directed repair while also increasing nonhomologous end-joining-dependent translocation frequency.

  PublisherDOI

• Mechanisms of insertions at a DNA double-strand break

  bioRxiv (Cold Spring Harbor Laboratory) · 2022-10-01

  preprintOpen access

  Abstract Insertions and deletions (indels) are common sources of structural variation, and insertions originating from spontaneous DNA lesions are frequent in cancer. We developed a highly sensitive assay in human cells (Indel-Seq) to monitor rearrangements at the TRIM37 acceptor locus which reports indels stemming from experimentally-induced and spontaneous genome instability. Templated insertions derive from sequences genome-wide and are enriched within 100 kb of donor regions flanking a DSB. Insertions require contact between donor and acceptor loci as well as DNA-PK catalytic activity. Notably, these templated insertions originate from actively transcribed loci, underscoring transcription as a critical source of spontaneous genome instability. Transcription-coupled insertions involve a DNA/RNA hybrid intermediate and are stimulated by DNA end-processing. Using engineered Cas9 breaks, we establish that ssDNA overhangs at the acceptor site greatly stimulate insertions. Indel-Seq revels that insertions are generated via at least three distinct pathways. Our studies indicate that insertions result from movement and subsequent contact between acceptor and donor loci followed invasion or annealing, then by non-homologous end-joining at the acceptor site.

  PublisherOA PDFDOI

• Single-molecule tracking reveals the functional allocation, <i>in vivo</i> interactions and spatial organization of universal transcription factor NusG

  bioRxiv (Cold Spring Harbor Laboratory) · 2022-11-22

  preprintOpen access

  Abstract Bacterial gene expression is highly regulated to allow cells to grow and adapt. Much regulation occurs during transcription elongation, where RNA polymerase (RNAP) extends nascent RNA transcripts aided by global and universally-conserved elongation factor NusG. NusG modulates transcription by inhibiting pausing and backtracking; promoting anti-termination on ribosomal RNA ( rrn ) operons; coupling transcription with translation on mRNA genes; and stimulating Rho-dependent termination on toxic genes. Despite extensive work on NusG, its functional allocation and spatial distribution in vivo is unknown. Here, we addressed these long-standing questions using single-molecule tracking and super-resolution imaging of NusG in live E. coli cells. We found that, under conditions of moderate growth, NusG is mainly present as a population that associates indirectly with the chromosome via RNAP in transcription elongation complexes, and a slowly diffusing population we identified as a NusG complex with the 30S ribosomal subunit; this complex offers a “30S-guided” path for NusG to enter transcription elongation. Only ~10% of total NusG was fast-diffusing, with the mobility of this population suggesting that free NusG interacts non-specifically with DNA for &gt;50% of the time. Using antibiotics and deletion mutants, we showed that most chromosome-associated NusG is involved in rrn anti-termination and in transcriptiontranslation coupling. NusG involvement in rrn anti-termination was mediated via its participation in phase-separated transcriptional condensates. Our work illuminates the diverse activities of a central regulator while offering a guide on how to dissect the roles of multi-functional machines using in vivo imaging.

  PublisherOA PDFDOI

• NusG links transcription and translation in <i>Escherichia coli</i> extracts

  bioRxiv (Cold Spring Harbor Laboratory) · 2021-07-31

  preprintOpen accessCorresponding

  Abstract In bacteria, transcription is coupled to, and can be regulated by, translation. Although recent structural studies suggest that the N-utilization substance G (NusG) transcription factor can serve as a direct, physical link between the transcribing RNA polymerase (RNAP) and the lead ribosome, mechanistic studies investigating the potential role of NusG in mediating transcription-translation coupling are lacking. Here, we report development of a cellular extract- and reporter gene-based, in vitro biochemical system that supports transcription-translation coupling as well as the use of this system to study the role of NusG in coupling. Our findings show that NusG is required for coupling and that the enhanced gene expression that results from coupling is dependent on the ability of NusG to directly interact with the lead ribosome. Moreover, we provide strong evidence that NusG-dependent coupling enhances gene expression through a mechanism in which the lead ribosome that is tethered to the RNAP by NusG suppresses spontaneous backtracking of the RNAP on its DNA template that would otherwise inhibit transcription.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01GM037219

  NIH · $11.2M · 2018

• NIH Grant R01GM03721926

  NIH · $400k · 2018

• Hormones: Molecular Mechanism of Action and Functions

  NIH · $9.9M · 1978–2026

• NIH Grant R56GM037219

  NIH · $399k · 2010

• NIH Grant R01DK050702

  NIH · $609k · 2000

Frequent coauthors

• Robert A. Weisberg

  National Institutes of Health

  63 shared

• Sankar Adhya

  National Cancer Institute

  56 shared

• Ira Pastan

  54 shared

• Enrico V. Avvedimento

  35 shared

• Donald L. Court

  National Cancer Institute

  34 shared

• Robert S. Washburn

  Columbia University Irving Medical Center

  32 shared

• Kazunori Shimada

  Juntendo University

  29 shared

• William S. Blaner

  28 shared

Labs

• Max E. Gottesman LabPI

Education

• B.A., Philosophy

  Swarthmore College

• M.D.

  Yale University

• Ph.D.

  Yale University

Awards & honors

• Jane Coffin Child Fund Fellow (1964-1966)
• Meritorious Executive Award, NCI (1982)
• Docteur Honoris Causa - Institut National des Science Appliq…
• Honorary Doctorate - Peking Union Medical College, Beijing,…
• Fellow, American Academy of Microbiology (2010)