Requirement for mevalonate in cycling cells: quantitative and temporal aspects

Area of Science:

• Cell Biology
• Biochemistry

Background:

• Isoprenoid compounds are essential for cellular processes.
• Mevalonate is a key precursor for isoprenoid biosynthesis.

Purpose of the Study:

• To investigate the requirement of isoprenoid compounds for cell cycle progression.
• To determine the specific role of mevalonate in DNA synthesis and cell division.

Main Methods:

• Cultured Chinese hamster ovary cells were treated with mevinolin to inhibit HMG-CoA reductase and mevalonate biosynthesis.
• Cell cycle arrest and DNA synthesis were monitored.
• Recovery of DNA synthesis was assessed by adding mevalonate and other compounds.
• 25-hydroxycholesterol was used to control HMG-CoA reductase induction.

Main Results:

• Mevinolin treatment caused G1 cell cycle arrest and inhibited DNA synthesis.
• Restoration of DNA synthesis required mevalonate, with optimal recovery at 200 µg/ml.
• Only a small fraction (0.1%) of total cellular isoprenoids derived from mevalonate was necessary for DNA synthesis recovery.
• Cholesterol was required for cell viability but not for DNA synthesis recovery.

Conclusions:

• A quantitatively minor product of mevalonate metabolism is critical for initiating DNA synthesis and cell cycle progression.
• This essential mevalonate-dependent event occurs early in the cell cycle, preceding other S phase requirements.