SCF ubiquitin E3 ligase regulates DNA double-strand breaks in early meiotic recombination

Author:

Guan Yongjuan1,Lin Huijuan12,Leu N Adrian1,Ruthel Gordon3,Fuchs Serge Y1ORCID,Busino Luca4,Luo Mengcheng2ORCID,Wang P Jeremy1ORCID

Affiliation:

1. Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA

2. Department of Tissue and Embryology, Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei Province, China

3. Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA

4. Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

Abstract

Abstract Homeostasis of meiotic DNA double strand breaks (DSB) is critical for germline genome integrity and homologous recombination. Here we demonstrate an essential role for SKP1, a constitutive subunit of the SCF (SKP1-Cullin-F-box) ubiquitin E3 ligase, in early meiotic processes. SKP1 restrains accumulation of HORMAD1 and the pre-DSB complex (IHO1-REC114-MEI4) on the chromosome axis in meiotic germ cells. Loss of SKP1 prior to meiosis leads to aberrant localization of DSB repair proteins and a failure in synapsis initiation in meiosis of both males and females. Furthermore, SKP1 is crucial for sister chromatid cohesion during the pre-meiotic S-phase. Mechanistically, FBXO47, a meiosis-specific F-box protein, interacts with SKP1 and HORMAD1 and targets HORMAD1 for polyubiquitination and degradation in HEK293T cells. Our results support a model wherein the SCF ubiquitin E3 ligase prevents hyperactive DSB formation through proteasome-mediated degradation of HORMAD1 and subsequent modulation of the pre-DSB complex during meiosis.

Funder

NIH

National Institute of Child Health and Human Development

National Cancer Institute

National Natural Science Foundation of China

Publisher

Oxford University Press (OUP)

Subject

Genetics

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