Ufd2p promotes efficient crossover formation by destabilizing Top2p during meiosis

Area of Science:

• Genetics
• Molecular Biology
• Cell Biology

Background:

• Crossover (CO) formation in meiosis is crucial for accurate chromosome segregation and genetic diversity.
• The molecular mechanisms governing CO number and distribution are not fully understood.
• The ubiquitin-proteasome system is implicated in CO regulation, but specific factors remain undefined.

Purpose of the Study:

• To identify novel regulators of CO formation in meiosis.
• To elucidate the molecular mechanisms by which Ufd2p influences CO frequency and distribution.
• To investigate the conserved role of UBE4B in CO formation across species.

Main Methods:

• Focused genetic screen in *Saccharomyces cerevisiae* to identify CO regulators.
• Integrated multiomics analysis to identify Ufd2p targets.
• Biochemical assays to assess ubiquitination and proteasomal degradation.
• Functional assays in yeast and mammalian cells to confirm conserved roles.

Main Results:

• Ufd2p was identified as a key regulator promoting efficient CO formation.
• Deletion of *UFD2* reduced CO frequency by enhancing CO interference.
• Ufd2p targets Topoisomerase II (Top2p) for ubiquitination and degradation.
• Top2p accumulation in *UFD2* deletion cells led to excessive resolution of DNA negative supercoils and reduced CO numbers.
• Mammalian UBE4B demonstrated a conserved role in CO formation by regulating TOP2A-dependent supercoil dynamics.
• Expression of UBE4B restored CO formation and meiotic progression in *UFD2* deletion yeast cells.

Conclusions:

• Ufd2p is a novel regulator of meiotic crossover formation.
• The Ufd2p-Top2p axis controls DNA supercoil homeostasis, impacting CO frequency and distribution.
• This mechanism is conserved across species, highlighting the fundamental importance of supercoil regulation in meiosis.