Sirt2-BubR1 acetylation pathway mediates the effects of advanced maternal age on oocyte quality

Area of Science:

• Reproductive Biology
• Molecular Biology
• Cell Biology

Background:

• Maternal aging is associated with oocyte meiotic defects, including aneuploidy.
• Reduced Sirtuin 2 (Sirt2) protein levels in aged oocytes correlate with these defects.
• The precise molecular mechanisms linking Sirt2 to oocyte quality during aging remain largely unknown.

Purpose of the Study:

• To elucidate the role of Sirt2 in mouse oocyte meiosis.
• To investigate the molecular targets and mechanisms through which Sirt2 influences oocyte quality.
• To determine if Sirt2-mediated pathways can counteract age-related meiotic errors.

Main Methods:

• Sirt2 depletion via knockdown in mouse oocytes.
• Analysis of oocyte maturation, spindle organization, and chromosome alignment.
• Investigation of kinetochore-microtubule attachment dynamics.
• Site-specific mutagenesis of BubR1 (BubR1-K243) to mimic or block acetylation.
• Overexpression of BubR1 mutants in Sirt2-depleted and aged oocytes.

Main Results:

• Sirt2 depletion impairs oocyte maturation, spindle organization, and kinetochore-microtubule attachments.
• Acetylation of BubR1 at lysine 243 (BubR1-K243) is critical for meiotic progression.
• Mimicking BubR1-K243 acetylation phenocopies Sirt2 depletion effects.
• Blocking BubR1-K243 acetylation partially rescues meiotic defects in Sirt2-depleted oocytes.
• Overexpressing a non-acetylatable BubR1 mutant (BubR1-K243R) in aged oocytes reduces aneuploidy.

Conclusions:

• Sirt2 regulates oocyte meiosis through the deacetylation of BubR1 at K243.
• This Sirt2-BubR1 pathway is essential for maintaining the integrity of the meiotic apparatus.
• Targeting this pathway offers a potential strategy to mitigate age-related declines in oocyte quality and fertility.