# Growth and differentiation in Bacillus subtilis

> **NIH NIH R35** · HARVARD MEDICAL SCHOOL · 2024 · $630,402

## Abstract

PROJECT SUMMARY/ABSTRACT
The proposed studies are part of our long-term effort to elucidate fundamental mechanisms underlying
chromosome dynamics and bacterial envelope biogenesis in the bacterium Bacillus subtilis.
Compaction of replicated chromosomes into morphologically and spatially distinct sister chromatids is
essential for faithful DNA segregation in all organisms. The goal of our research is to broadly elucidate how B.
subtilis organizes and segregates its chromosomes but we have placed particular emphasis on defining the
activity and function of the broadly conserved SMC condensin complex in these processes. Our studies have
revealed that these ring-shaped ATPases extrude DNA loops. Loop extrusion ensures that these complexes
act in cis drawing DNA in on itself and away from its sister chromosome. This activity can explain how SMC
complexes can resolve newly replicated origins in bacteria and sister chromatids in eukaryotes. Our future
research seeks to establish whether loop extrusion mediates origin resolution and the extent to which it drives
the dynamic rearrangements of the chromosome during the replication-segregation cycle. Separately, we will
define the molecular basis for site-specific unloading of SMC complexes by XerD at the replication terminus.
Analysis of chromosome dynamics in this simple bacterial system will provide mechanistic insight and a level
of resolution not possible in more complex organisms.
The bacterial cell wall peptidoglycan (PG) is composed of long glycan strands cross-linked together by short
peptides. This three-dimensional meshwork protects the cell from osmotic lysis, determines shape, and its
assembly is the target of some of our most successful antibiotics. Accordingly, a deeper understanding of cell
wall biogenesis has broad implications for both basic bacterial cell biology and therapeutic development.
Research over the last half century has identified virtually all the factors involved in envelope assembly. A
major gap in our knowledge is how these enzymes are coordinated with each other and how the cell monitors
the envelope for defects and directs their repair. Our future research is focused on three signal transduction
pathways that play central roles in these processes. The WalR-WalK two-component signaling system is
involved in the homeostatic control of cell wall hydrolases required for growth. The SigI-RsgI pathway
monitors the cell wall meshwork and induces PG remodeling enzymes when it identifies defects. Finally, the
SigM-YhdLK pathway monitors the universal lipid carrier undecaprenyl-phosphate and prioritizes its use for
cell wall synthesis. We seek to define how these pathways function in molecular detail. Our findings will
provide broadly relevant principles for envelope assembly and maintenance in all bacteria.

## Key facts

- **NIH application ID:** 10872272
- **Project number:** 5R35GM145299-03
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** DAVID Z RUDNER
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $630,402
- **Award type:** 5
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10872272

## Citation

> US National Institutes of Health, RePORTER application 10872272, Growth and differentiation in Bacillus subtilis (5R35GM145299-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10872272. Licensed CC0.

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