EfgA is a conserved formaldehyde sensor that leads to bacterial growth arrest in response to elevated formaldehyde

Normal cellular processes give rise to toxic metabolites that cells must mitigate. Formaldehyde is a universal stressor and potent metabolic toxin that is generated in organisms from bacteria to humans. Methylotrophic bacteria such as Methylorubrum extorquens face an acute challenge due to their production of formaldehyde as an obligate central intermediate of single-carbon metabolism. Mechanisms to sense and respond to formaldehyde were speculated to exist in methylotrophs for decades but had never been discovered. Here, we identify a member of the DUF336 domain family, named efgA for enhanced formaldehyde growth, that plays an important role in endogenous formaldehyde stress response in M. extorquens PA1 and is found almost exclusively in methylotrophic taxa. Our experimental analyses reveal that EfgA is a formaldehyde sensor that rapidly arrests growth in response to elevated levels of formaldehyde. Heterologous expression of EfgA in Escherichia coli increases formaldehyde resistance, indicating that its interaction partners are widespread and conserved. EfgA represents the first example of a formaldehyde stress response system that does not involve enzymatic detoxification. Thus, EfgA comprises a unique stress response mechanism in bacteria, whereby a single protein directly senses elevated levels of a toxic intracellular metabolite and safeguards cells from potential damage.

Download Full-text

EfgA is a conserved formaldehyde sensor that halts bacterial translation in response to elevated formaldehyde

10.1101/2020.10.16.343392 ◽

2020 ◽

Author(s):

Jannell V. Bazurto ◽

Dipti D. Nayak ◽

Tomislav Ticak ◽

Milya Davlieva ◽

Jessica A. Lee ◽

...

Keyword(s):

Stress Response ◽

Methylotrophic Bacteria ◽

Translational Machinery ◽

Cellular Processes ◽

Translational Activity ◽

Interaction Partners ◽

Single Protein ◽

Stress Response System ◽

Sense And Respond ◽

Enzymatic Detoxification

AbstractNormal cellular processes give rise to toxic metabolites that cells must mitigate. Formaldehyde is a universal stressor and potent metabolic toxin that is generated in organisms from bacteria to humans. Methylotrophic bacteria such as Methylorubrum extorquens face an acute challenge due to their production of formaldehyde as an obligate central intermediate of single-carbon metabolism. Mechanisms to sense and respond to formaldehyde were speculated to exist in methylotrophs for decades but had never been discovered. Here we identify a member of the DUF336 domain family, named efgA for enhanced formaldehyde growth, that plays an important role in endogenous formaldehyde stress response in M. extorquens PA1 and is found almost exclusively in methylotrophic taxa. Our experimental analyses reveal that EfgA is a formaldehyde sensor that inhibits translation in response to elevated levels of formaldehyde. Heterologous expression of EfgA in Escherichia coli increases formaldehyde resistance, indicating that its interaction partners are widespread and conserved and may include translational machinery. EfgA represents the first example of a formaldehyde stress response system that does not involve enzymatic detoxification. Thus, EfgA comprises a unique stress response mechanism in bacteria, whereby a single protein directly senses elevated levels of a toxic intracellular metabolite and modulates translational activity.

Download Full-text

Past Child Abuse Plus Variations in Gene Result in Potent PTSD Risk for Adults: Combined Factors May Change Biology of Stress-Response System as it Develops

PsycEXTRA Dataset ◽

10.1037/e423102008-001 ◽

2008 ◽

Keyword(s):

Child Abuse ◽

Stress Response ◽

Response System ◽

Stress Response System

Download Full-text

Systematic Humanization of the Yeast Cytoskeleton Discerns Functionally Replaceable from Divergent Human Genes

Genetics ◽

10.1534/genetics.120.303378 ◽

2020 ◽

Vol 215 (4) ◽

pp. 1153-1169 ◽

Cited By ~ 1

Author(s):

Riddhiman K. Garge ◽

Jon M. Laurent ◽

Aashiq H. Kachroo ◽

Edward M. Marcotte

Keyword(s):

Gene Families ◽

Growth Defect ◽

Gene Duplications ◽

Yeast Gene ◽

Macromolecular Transport ◽

Cellular Processes ◽

Growth Defects ◽

Yeast Strains ◽

Human Genes ◽

Interaction Partners

Many gene families have been expanded by gene duplications along the human lineage, relative to ancestral opisthokonts, but the extent to which the duplicated genes function similarly is understudied. Here, we focused on structural cytoskeletal genes involved in critical cellular processes, including chromosome segregation, macromolecular transport, and cell shape maintenance. To determine functional redundancy and divergence of duplicated human genes, we systematically humanized the yeast actin, myosin, tubulin, and septin genes, testing ∼81% of human cytoskeletal genes across seven gene families for their ability to complement a growth defect induced by inactivation or deletion of the corresponding yeast ortholog. In five of seven families—all but α-tubulin and light myosin, we found at least one human gene capable of complementing loss of the yeast gene. Despite rescuing growth defects, we observed differential abilities of human genes to rescue cell morphology, meiosis, and mating defects. By comparing phenotypes of humanized strains with deletion phenotypes of their interaction partners, we identify instances of human genes in the actin and septin families capable of carrying out essential functions, but failing to fully complement the cytoskeletal roles of their yeast orthologs, thus leading to abnormal cell morphologies. Overall, we show that duplicated human cytoskeletal genes appear to have diverged such that only a few human genes within each family are capable of replacing the essential roles of their yeast orthologs. The resulting yeast strains with humanized cytoskeletal components now provide surrogate platforms to characterize human genes in simplified eukaryotic contexts.

Download Full-text

Functional Roles of Bromodomain Proteins in Cancer

Cancers ◽

10.3390/cancers13143606 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3606

Author(s):

Samuel P. Boyson ◽

Cong Gao ◽

Kathleen Quinn ◽

Joseph Boyd ◽

Hana Paculova ◽

...

Keyword(s):

Open Chromatin ◽

Structural Domains ◽

Pharmacological Agents ◽

Functional Roles ◽

Cellular Processes ◽

Protein Interactome ◽

Interaction Partners ◽

Recent Developments ◽

Bromodomain Proteins ◽

Chromatin Configuration

Histone acetylation is generally associated with an open chromatin configuration that facilitates many cellular processes including gene transcription, DNA repair, and DNA replication. Aberrant levels of histone lysine acetylation are associated with the development of cancer. Bromodomains represent a family of structurally well-characterized effector domains that recognize acetylated lysines in chromatin. As part of their fundamental reader activity, bromodomain-containing proteins play versatile roles in epigenetic regulation, and additional functional modules are often present in the same protein, or through the assembly of larger enzymatic complexes. Dysregulated gene expression, chromosomal translocations, and/or mutations in bromodomain-containing proteins have been correlated with poor patient outcomes in cancer. Thus, bromodomains have emerged as a highly tractable class of epigenetic targets due to their well-defined structural domains, and the increasing ease of designing or screening for molecules that modulate the reading process. Recent developments in pharmacological agents that target specific bromodomains has helped to understand the diverse mechanisms that bromodomains play with their interaction partners in a variety of chromatin processes, and provide the promise of applying bromodomain inhibitors into the clinical field of cancer treatment. In this review, we explore the expression and protein interactome profiles of bromodomain-containing proteins and discuss them in terms of functional groups. Furthermore, we highlight our current understanding of the roles of bromodomain-containing proteins in cancer, as well as emerging strategies to specifically target bromodomains, including combination therapies using bromodomain inhibitors alongside traditional therapeutic approaches designed to re-program tumorigenesis and metastasis.

Download Full-text