Cell-type-specific nucleotide sharing through gap junctions impacts sensitivity to replication stress in Drosophila

Area of Science:

• Cell Biology
• Developmental Biology
• Molecular Biology

Background:

• Cell proliferation requires abundant deoxynucleotides (dNTPs) for DNA synthesis.
• Cellular dNTP levels are typically regulated by intrinsic de novo synthesis and salvage pathways.
• Non-autonomous provision of metabolites between cells is a potential, yet understudied, mechanism for maintaining tissue homeostasis.

Purpose of the Study:

• To investigate the role of intercellular communication in maintaining deoxynucleotide (dNTP) pool homeostasis.
• To determine if cells can receive dNTPs from neighboring cells in vivo.
• To understand differential sensitivity of various cell types to nucleotide depletion.

Main Methods:

• Utilized Drosophila epithelial tissues, including adult intestinal stem cells (ISCs) and wing progenitor cells, as model systems.
• Examined the role of gap junctions in intercellular metabolite exchange.
• Assessed cellular sensitivity to nucleotide depletion and replication stress.

Main Results:

• Demonstrated that nucleotides can be supplied to cells non-autonomously via gap junction connections.
• Wing progenitor cells, possessing gap junctions, buffered against nucleotide depletion-induced replication stress.
• Adult ISCs, lacking gap junctions, were highly sensitive to nucleotide depletion due to inability to receive dNTPs from neighbors.

Conclusions:

• Gap junction-dependent intercellular sharing contributes significantly to deoxynucleotide (dNTP) pool homeostasis in vivo.
• Differential expression and permeability of gap junctions influence cellular sensitivity to fluctuations in intracellular dNTP levels.
• This highlights a novel mechanism for metabolic cooperation in maintaining tissue health and function.