MDC1 is Essential for G2/M Transition and Spindle Assembly in Mouse Oocytes

Overview

Journal Cell Mol Life Sci

Publisher Springer

Specialty Biology

Date 2022 Mar 23

PMID 35320416

Authors

Jiyeon Leem

Jeong Su Oh

Affiliations

Soon will be listed here.

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.

Citing Articles

Distinct characteristics of the DNA damage response in mammalian oocytes.

Leem J, Lee C, Choi D, Oh J Exp Mol Med. 2024; 56(2):319-328.

PMID: 38355825 PMC: 10907590. DOI: 10.1038/s12276-024-01178-2.

Oocytes can repair DNA damage during meiosis via a microtubule-dependent recruitment of CIP2A-MDC1-TOPBP1 complex from spindle pole to chromosomes.

Leem J, Kim J, Oh J Nucleic Acids Res. 2023; 51(10):4899-4913.

PMID: 36999590 PMC: 10250218. DOI: 10.1093/nar/gkad213.

Selective utilization of non-homologous end-joining and homologous recombination for DNA repair during meiotic maturation in mouse oocytes.

Lee C, Leem J, Oh J Cell Prolif. 2022; 56(4):e13384.

PMID: 36564861 PMC: 10068936. DOI: 10.1111/cpr.13384.

References

Krenning L, Feringa F, Shaltiel I, van den Berg J, Medema R . Transient activation of p53 in G2 phase is sufficient to induce senescence. Mol Cell. 2014; 55(1):59-72. DOI: 10.1016/j.molcel.2014.05.007. View

Marangos P, Stevense M, Niaka K, Lagoudaki M, Nabti I, Jessberger R . DNA damage-induced metaphase I arrest is mediated by the spindle assembly checkpoint and maternal age. Nat Commun. 2015; 6:8706. PMC: 4667640. DOI: 10.1038/ncomms9706. View

Li Z, Shao C, Kong Y, Carlock C, Ahmad N, Liu X . DNA Damage Response-Independent Role for MDC1 in Maintaining Genomic Stability. Mol Cell Biol. 2017; 37(9). PMC: 5394279. DOI: 10.1128/MCB.00595-16. View

Schuh M, Ellenberg J . Self-organization of MTOCs replaces centrosome function during acentrosomal spindle assembly in live mouse oocytes. Cell. 2007; 130(3):484-98. DOI: 10.1016/j.cell.2007.06.025. View

Blackford A, Jackson S . ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response. Mol Cell. 2017; 66(6):801-817. DOI: 10.1016/j.molcel.2017.05.015. View

Adhikari D, Busayavalasa K, Zhang J, Hu M, Risal S, Bayazit M . Inhibitory phosphorylation of Cdk1 mediates prolonged prophase I arrest in female germ cells and is essential for female reproductive lifespan. Cell Res. 2016; 26(11):1212-1225. PMC: 5099868. DOI: 10.1038/cr.2016.119. View

Polo S, Jackson S . Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. Genes Dev. 2011; 25(5):409-33. PMC: 3049283. DOI: 10.1101/gad.2021311. View

Bartek J, Lukas J . DNA damage checkpoints: from initiation to recovery or adaptation. Curr Opin Cell Biol. 2007; 19(2):238-45. DOI: 10.1016/j.ceb.2007.02.009. View

Coster G, Hayouka Z, Argaman L, Strauss C, Friedler A, Brandeis M . The DNA damage response mediator MDC1 directly interacts with the anaphase-promoting complex/cyclosome. J Biol Chem. 2007; 282(44):32053-64. DOI: 10.1074/jbc.M705890200. View

10.

Bartek J, Lukas J . Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell. 2003; 3(5):421-9. DOI: 10.1016/s1535-6108(03)00110-7. View

11.

Mullers E, Silva Cascales H, Jaiswal H, Saurin A, Lindqvist A . Nuclear translocation of Cyclin B1 marks the restriction point for terminal cell cycle exit in G2 phase. Cell Cycle. 2014; 13(17):2733-43. PMC: 4615111. DOI: 10.4161/15384101.2015.945831. View

12.

Panier S, Boulton S . Double-strand break repair: 53BP1 comes into focus. Nat Rev Mol Cell Biol. 2013; 15(1):7-18. DOI: 10.1038/nrm3719. View

13.

Holt J, Tran S, Stewart J, Minahan K, Garcia-Higuera I, Moreno S . The APC/C activator FZR1 coordinates the timing of meiotic resumption during prophase I arrest in mammalian oocytes. Development. 2011; 138(5):905-13. DOI: 10.1242/dev.059022. View

14.

Soderberg O, Gullberg M, Jarvius M, Ridderstrale K, Leuchowius K, Jarvius J . Direct observation of individual endogenous protein complexes in situ by proximity ligation. Nat Methods. 2006; 3(12):995-1000. DOI: 10.1038/nmeth947. View

15.

Carroll J, Marangos P . The DNA damage response in mammalian oocytes. Front Genet. 2013; 4:117. PMC: 3690358. DOI: 10.3389/fgene.2013.00117. View

16.

Celeste A, Fernandez-Capetillo O, Kruhlak M, Pilch D, Staudt D, Lee A . Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks. Nat Cell Biol. 2003; 5(7):675-9. DOI: 10.1038/ncb1004. View

17.

Holt J, Weaver J, Jones K . Spatial regulation of APCCdh1-induced cyclin B1 degradation maintains G2 arrest in mouse oocytes. Development. 2010; 137(8):1297-304. DOI: 10.1242/dev.047555. View

18.

Eliezer Y, Argaman L, Kornowski M, Roniger M, Goldberg M . Interplay between the DNA damage proteins MDC1 and ATM in the regulation of the spindle assembly checkpoint. J Biol Chem. 2014; 289(12):8182-93. PMC: 3961647. DOI: 10.1074/jbc.M113.532739. View

19.

Namgoong S, Kim N . Meiotic spindle formation in mammalian oocytes: implications for human infertility. Biol Reprod. 2018; 98(2):153-161. DOI: 10.1093/biolre/iox145. View

20.

Barra V, Fachinetti D . The dark side of centromeres: types, causes and consequences of structural abnormalities implicating centromeric DNA. Nat Commun. 2018; 9(1):4340. PMC: 6194107. DOI: 10.1038/s41467-018-06545-y. View