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MDC1 is essential for G2/M transition and spindle assembly in mouse oocytes

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Abstract

Mammalian oocytes are particularly susceptible to accumulating DNA damage. However, unlike mitotic cells in which DNA damage induces G2 arrest by activating the ATM-Chk1/2-Cdc25 pathway, oocytes readily enter M-phase immediately following DNA damage. This implies a lack of a robust canonical G2/M DNA damage checkpoint in oocytes. Here we show that MDC1 plays a non-canonical role in controlling G2/M transition by regulating APC/C-Cdh1-mediated cyclin B1 degradation in response to DNA damage in mouse oocytes. Depletion of MDC1 impaired M-phase entry by decreasing cyclin B1 levels via the APC/C-Cdh1 pathway. Notably, the APC/C-Cdh1 regulation mediated by MDC1 was achieved by a direct interaction between MDC1 and APC/C-Cdh1. This interaction was transiently disrupted after DNA damage with a concomitant increase in Cdh1 levels, which, in turn, decreased cyclin B1 levels and delayed M-phase entry. Moreover, MDC1 depletion impaired spindle assembly by decreasing the integrity of microtubule organizing centers (MTOCs). Therefore, our results demonstrate that MDC1 is an essential molecule in regulating G2/M transition in response to DNA damage and in regulating spindle assembly in mouse oocytes. These results provide new insights into the regulation of the G2/M DNA damage checkpoint and cell cycle control in oocytes.

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The authors confirmed that all data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Funding

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2017R1A6A1A03015642 and NRF-2019R1I1A2A01041413).

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Authors and Affiliations

  1. Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Korea

    Jiyeon Leem & Jeong Su Oh

  2. Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon, Korea

    Jeong Su Oh

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  1. Jiyeon Leem
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  2. Jeong Su Oh
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JL and JSO conceived and designed the experiments. JL performed all experiments. JL and JSO analyzed and interpreted the data. JSO supervised the study. JL and JSO wrote the manuscript.

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Correspondence to Jeong Su Oh.

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Leem, J., Oh, J.S. MDC1 is essential for G2/M transition and spindle assembly in mouse oocytes. Cell. Mol. Life Sci. 79, 200 (2022). https://doi.org/10.1007/s00018-022-04241-1

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