Regulated Proteolysis of MutSγ Controls Meiotic Crossing Over.

Abstract:

:Crossover recombination is essential for accurate chromosome segregation during meiosis. The MutSγ complex, Msh4-Msh5, facilitates crossing over by binding and stabilizing nascent recombination intermediates. We show that these activities are governed by regulated proteolysis. MutSγ is initially inactive for crossing over due to an N-terminal degron on Msh4 that renders it unstable by directly targeting proteasomal degradation. Activation of MutSγ requires the Dbf4-dependent kinase Cdc7 (DDK), which directly phosphorylates and thereby neutralizes the Msh4 degron. Genetic requirements for Msh4 phosphorylation indicate that DDK targets MutSγ only after it has bound to nascent joint molecules (JMs) in the context of synapsing chromosomes. Overexpression studies confirm that the steady-state level of Msh4, not phosphorylation per se, is the critical determinant for crossing over. At the DNA level, Msh4 phosphorylation enables the formation and crossover-biased resolution of double-Holliday Junction intermediates. Our study establishes regulated protein degradation as a fundamental mechanism underlying meiotic crossing over.

journal_name

Mol Cell

journal_title

Molecular cell

authors

He W,Rao HBDP,Tang S,Bhagwat N,Kulkarni DS,Ma Y,Chang MAW,Hall C,Bragg JW,Manasca HS,Baker C,Verhees GF,Ranjha L,Chen X,Hollingsworth NM,Cejka P,Hunter N

doi

10.1016/j.molcel.2020.02.001

subject

Has Abstract

pub_date

2020-04-02 00:00:00

pages

168-183.e5

issue

1

eissn

1097-2765

issn

1097-4164

pii

S1097-2765(20)30071-X

journal_volume

78

pub_type

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