Reproductive lifespan in females relies on the size of the resting oocyte pool. Excessive atresia of oocytes occurs in response to defects in meiotic prophase and extraneous DNA damage such as cancer radiotherapy and chemotherapy. For instance, oocyte pools in mouse Spo11 mutants are eliminated within three months because Spo11-/- fails to initiate recombination and pair up homologous chromosomes. In Msh4 mutants, recombination is initiated, but progression of recombination and homolog pairing/synapsis are defective. The oocyte pools of Msh4-/- are depleted within four days of birth. Two distinct branches of the meiotic checkpoint pathway are inferred to respond to defects in recombination or homolog pairing, respectively. Several components of the DNA damage response (DDR) define the meiotic response to unrepaired recombination intermediates. In contrast, the response to defective synapsis requires a meiosis-specific factor, HORMAD1, and provokes transcriptional silencing via a process termed Meiotic Silencing of Unpaired Chromatin (MSUC). I have identified RNF212 as a novel component of the meiotic checkpoint machinery. Strikingly, Rnf212 mutation restores the resting oocyte pools in both Spo11-/- and Msh4-/- backgrounds. Intriguingly, Rnf212 encodes an RING-family E3-ligase that catalyzes a protein modification by the Small Ubiquitin-like Molecule, SUMO. These data imply that RNF212-mediated SUMOylation is a key aspect of the meiotic checkpoint-signaling pathway that leads to oocyte apoptosis. I will investigate the nature and mechanism of RNF212-dependent oocyte quality control in mouse using a combination of genetics, cell biology and molecular approaches. These studies will build the foundation for research in my own laboratory that will pursue a mechanistic understanding of gamete quality control.
Aim1 is to determine the efficiency of oocyte rescue in synapsis/recombination mutants and whether RNF212 contributes to physiological post-partum atresia. In the Spo11-/-, Spo11-/-Rnf212-/-, Msh4-/-, and Msh4-/-Rnf212-/- mutant backgrounds, total numbers of oocytes and developing follicles will be quantified in the ovaries of newborns and animals of various ages.
Aim 2 is to understand how Rnf212 mutation rescues oocyte pools in synapsis/recombination mutants. A number of models could explain how Rnf212 mutation can bypass oocyte loss in synapsis and recombination mutants. To begin to distinguish between these models, I will perform a detailed characterization of meiotic prophase in fetal ovaries.
Aim 3 is to identify targets of RNF212-mediated SUMOylation involved in the meiotic checkpoint. Understanding the role of RNF212 in meiotic checkpoint signaling will require identification of pertinent target proteins. In this aim, I will identify RNF212 targets through a combination of candidate and unbiased approaches using western blot, yeast-two-hybrid and proteomics approaches.

Public Health Relevance

Reproductive life span varies among human females. Radiation- and chemotherapies reduce the reproductive life span of female cancer patients. RNF212 is a novel factor that enforces the elimination of oocytes with meiotic defects and may be related to reproductive lifespan, fertility, miscarriage, and birth defects. Revealing the role of RNF212 in the meiotic checkpoint pathway will help us better understand and treat the above conditions.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Career Transition Award (K99)
Project #
Application #
Study Section
Biobehavioral and Behavioral Sciences Subcommittee (CHHD)
Program Officer
Taymans, Susan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Davis
Schools of Medicine
United States
Zip Code
Qiao, Huanyu; Rao, H B D Prasada; Yun, Yan et al. (2018) Impeding DNA Break Repair Enables Oocyte Quality Control. Mol Cell 72:211-221.e3