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

Leem, Jiyeon; Oh, Jeong Su

doi:10.1007/s00018-022-04241-1

Cited by 4 publications

(6 citation statements)

References 38 publications

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“…2C; Fig. S1), consistent with a previous report that MDC1 regulates CEP192-mediated microtubuleorganizing center (MTOC) assembly during oocyte meiosis [26]. However, after ETP treatment, p-MDC1 signals were enriched in chromosomes (Fig.…”

Section: Dsbs Induce Chromosomal Recruitment Of Mdc1 and Spindle Shri...supporting

confidence: 91%

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

Leem

Kim

2022

Preprint

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Because DNA double-strand breaks (DSBs) greatly threaten genomic integrity, effective DNA damage sensing and repair are essential for cellular survival in all organisms. However, DSB repair mainly occurs during the interphase and is repressed during mitosis. Here, we show that, unlike mitotic cells, oocytes can repair DSBs during meiosis through microtubule-dependent chromosomal recruitment of the CIP2A-MDC1-TOPBP1 complex from spindle poles. After DSB induction, we observed spindle shrinkage and stabilization, as well as BRCA1 and 53BP1 recruitment to chromosomes and subsequent DSB repair during meiosis I. Moreover, p-MDC1 and p-TOPBP1 were recruited from spindle poles to chromosomes in a CIP2A-dependent manner. This pole-to-chromosome relocation of the CIP2A-MDC1-TOPBP1 complex was impaired not only by depolymerizing microtubules but also by depleting CENP-A or HEC1, indicating that the kinetochore/centromere serves as a structural hub for microtubule-dependent transport of the CIP2A-MDC1-TOPBP1 complex. Mechanistically, DSB-induced CIP2A-MDC1-TOPBP1 relocation is regulated by PLK1 but not by ATM activity. Our data provide new insights into the critical crosstalk between chromosomes and spindle microtubules in response to DNA damage to maintain genomic stability during oocyte meiosis.

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Section: Dsbs Induce Chromosomal Recruitment Of Mdc1 and Spindle Shri...supporting

confidence: 91%

“…Chromosome spreads were prepared as previously described [26, 50]. Briefly, MI oocytes were exposed to acidic Tyrode’s solution (pH 2.5) for 2–3 min to remove the zona pellucida.…”

Section: Methodsmentioning

confidence: 99%

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

Leem

Kim

2022

Preprint

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“…However, it should be noted that the APC/C-mediated G2/M checkpoint does not occur rapidly in response to DNA damage. In line with this, it has been reported that MDC1 plays a crucial role in regulating the APC/C-Cdh1-mediated G2/M checkpoint in mouse oocytes 56 . MDC1 directly interacts with APC/C-Cdh1 to exert this control.…”

Section: Distinct Features Of the Dna Damage Response In Oocytessupporting

confidence: 58%

“…MDC1 directly interacts with APC/C-Cdh1 to exert this control. Notably, this novel interaction between MDC1 and APC/C-Cdh1 is disrupted by DNA damage and increases APC/C-Cdh1 activity, which in turn delays meiotic resumption 56 . In addition to the above mechanisms, the G2/prophase DNA damage checkpoint in oocytes becomes more robust when the oocyte is surrounded by a layer of cumulus cells.…”

Section: Distinct Features Of the Dna Damage Response In Oocytesmentioning

confidence: 99%

Distinct characteristics of the DNA damage response in mammalian oocytes

Leem,

Lee,

Choi

et al. 2024

Exp Mol Med

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DNA damage is a critical threat that poses significant challenges to all cells. To address this issue, cells have evolved a sophisticated molecular and cellular process known as the DNA damage response (DDR). Among the various cell types, mammalian oocytes, which remain dormant in the ovary for extended periods, are particularly susceptible to DNA damage. The occurrence of DNA damage in oocytes can result in genetic abnormalities, potentially leading to infertility, birth defects, and even abortion. Therefore, understanding how oocytes detect and repair DNA damage is of paramount importance in maintaining oocyte quality and preserving fertility. Although the fundamental concept of the DDR is conserved across various cell types, an emerging body of evidence reveals striking distinctions in the DDR between mammalian oocytes and somatic cells. In this review, we highlight the distinctive characteristics of the DDR in oocytes and discuss the clinical implications of DNA damage in oocytes.

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“…The failure to preserve centromere integrity further impairs kinetochore assembly and SAC activation, resulting in the bypass of SAC arrest. Because p‐MDC1 is localized at the spindle pole during oocyte meiosis, 32 the decrease in MDC1 and TUNEL signals after B02 treatment during meiotic maturation of oocytes with DNA damage is likely associated with impaired centromere and chromosome architecture. Moreover, weakened centromeres tend to be fragmented due to the increased centromere tension generated by the pulling force of spindle microtubules during chromosome segregation.…”

Section: Discussionmentioning

confidence: 99%

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

Lee

Leem

2022

Cell Proliferation

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DNA double-strand breaks (DSBs) are highly toxic lesions that can cause genomic instability and can be repaired by non-homologous end-joining (NHEJ) and homologous recombination (HR) pathways. Despite extensive studies about DSB repair pathways, the roles of each pathway during meiotic maturation in oocytes are not well understood. Here we show that oocytes selectively utilize NHEJ and HR to repair DSBs during meiotic maturation. Inhibition of NHEJ impaired the meiotic maturation of oocytes with DNA damage by activating the spindle assembly checkpoint (SAC) with a concomitant increase in metaphase I (MI) arrest and DNA damage levels. In contrast, oocytes with DNA damage bypassed SAC-mediated MI arrest despite the presence of fragmented DNA when HR was inhibited. Notably, this bypass of SAC arrest by HR inhibition was associated with a loss of centromere integrity and subsequent impairment of chromosome architecture. Our results demonstrate that, while NHEJ is critical for the meiotic maturation of oocytes with DNA damage, HR is essential to maintain centromere integrity against DNA damage during meiotic maturation, revealing distinct roles of NHEJ and HR during meiotic maturation in mouse oocytes. | INTRODUCTIONDNA double-strand breaks (DSBs) are one of the most deleterious types of DNA damage and often occur naturally through various endogenous and exogenous processes. However, cells are able to cope with DSBs using well-equipped repair pathways to maintain genome integrity. DSBs are primarily repaired by two mechanisms: non-homologous end-joining (NHEJ) and homologous recombination (HR). 1 NHEJ is initiated by the recognition and binding of the Ku70/80 heterodimer to DNA ends, followed by recruitment of the main NHEJ repair factors, including DNA-dependent protein kinase catalytic subunit (DNA-PKcs), Artemis and DNA ligase IV. 2 Because DSB ends are directly ligated without the use of a homologous template, NHEJ is generally considered error-prone. By contrast, HR tends to be error-free because broken ends are repaired using homologous sequences as templates. Also, HR is a more complex process involving 5 0 -end resections to generate 3 0 -single-stranded (ss) DNA overhangs. 3 This processing is initiated by the binding of the heterotrimeric Mre11-Rad50-Nbs1 (MRN) complex to DSBs, which coordinates tethering and short-range nucleolytic degradation of DSB ends by activating the endo-and exonuclease activity of Mre11. After 5 0end-resection, the 3'-ssDNA overhangs are rapidly coated by RPA, which is subsequently displaced by Rad51, forming presynaptic filaments that facilitate the search for homologous DNA templates for Crystal Lee and Jiyeon Leem contributed equally to this work.

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

Cited by 4 publications

References 38 publications

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

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

Distinct characteristics of the DNA damage response in mammalian oocytes

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

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