"In the study, Ben-Sahra and his collaborators focused on an enzyme called succinate dehydrogenase (SDH), a key part of the mitochondria - the cell's "power plants." Investigators found that when they blocked SDH using CRISPR-Cas9 gene editing or chemical drugs, cells struggled to make purines, the molecules that form DNA and RNA. Without purines, cells cannot multiply efficiently."
"Investigators also observed that when SDH is inhibited, the level of succinate rises. This excess succinate interferes with another enzyme, SHMT2, which usually helps produce molecules needed for purine assembly. With SHMT2 slowed down, the cell's purine production stalls."
"However, blocking this process doesn't stop cancer cells, investigators found. Instead, the cancer cells switch to a backup system known as the purine salvage pathway, in which the cells recycle old purines to keep growing. The study investigators realized this adaptation could be exploited: if both SDH and the salvage pathway are blocked at the same time, cancer cells would lose their ability to build DNA altogether."
Blocking succinate dehydrogenase (SDH), a mitochondrial enzyme, causes cells to struggle to synthesize purines required for DNA and RNA. SDH inhibition elevates succinate levels that interfere with SHMT2, reducing production of one-carbon units needed for purine assembly and stalling purine synthesis. Cancer cells compensate by switching to the purine salvage pathway to recycle nucleotides and maintain proliferation. Simultaneous inhibition of SDH and the salvage pathway removes both de novo and recycled purine supply, depriving cells of DNA building blocks and halting their ability to multiply.
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