Maternal DCAF2 is crucial for maintenance of genome stability during the first cell cycle in mice

Xu, Yiwen; Cao, Lan-Rui; Wang, Min; Xu, Ying; Wu, Xin; Liu, Junping; Tong, Chao; Fan, Heng‐Yu

doi:10.1242/jcs.206664

Cited by 19 publications

(12 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The double DNA content per se may not be blamed for the 2-cell arrest of COPS3inactivated embryos, since tetraploid embryos form blastocysts 53 , whereas genotoxic stress (DNA damage) is well-known to cause 2-cell arrest 54 . Similar effects on DNA replication and repair in 2cell mouse embryos have previously been reported after genetic ablation of DDB1-and CUL4associated factor 2 (Dcaf2) and Cullin 1 (Cul1) [55][56][57][58] , however, the operating mode of COPS3 may or may not be the same. Whereas the inactivation of CUL1 resulted in an accumulation of pan-CYCLIN E 55 , the inactivation of COPS3 resulted in an accumulation of Cyclin E2 mRNA but not of Cyclin E1 mRNA; and whereas COPS3 features a cortical deposit in oocytes, this structure could not be demonstrated in Dcaf2-deficient oocytes (due to the lack of a suitable antibody) and the microinjection of mCherry-tagged Dcaf2 mRNA in oocytes did not result in the assembly of a cortical rim 56 .…”

Section: Discussionsupporting

confidence: 56%

“…Similar effects on DNA replication and repair in 2cell mouse embryos have previously been reported after genetic ablation of DDB1-and CUL4associated factor 2 (Dcaf2) and Cullin 1 (Cul1) [55][56][57][58] , however, the operating mode of COPS3 may or may not be the same. Whereas the inactivation of CUL1 resulted in an accumulation of pan-CYCLIN E 55 , the inactivation of COPS3 resulted in an accumulation of Cyclin E2 mRNA but not of Cyclin E1 mRNA; and whereas COPS3 features a cortical deposit in oocytes, this structure could not be demonstrated in Dcaf2-deficient oocytes (due to the lack of a suitable antibody) and the microinjection of mCherry-tagged Dcaf2 mRNA in oocytes did not result in the assembly of a cortical rim 56 . Refining the mechanistic picture of the role of COPS3 in DNA metabolism, our study also indicated possible mediators of the nuclear DNA phenotype: Downregulation of genes such as Geminin and Brcc3, which superintend to DNA endoreduplication and DNA repair, respectively.…”

Section: Discussionsupporting

confidence: 56%

See 1 more Smart Citation

A Critical Role for The COP9 Signalosome Subunit 3 as A Gatekeeper of Genome Integrity in 2-Cell Mouse Embryos

Israel

Drexler

Fuellen

et al. 2021

Preprint

View full text Add to dashboard Cite

Investigations of genes required in early mammalian development are complicated by protein deposits of maternal products, which continue to operate after the gene locus has been disrupted. This leads to an underestimation of the number of genes known to be needed during the embryonic phase of cellular totipotency (up to the 4-cell stage). Here, we expose a critical role of the gene Cops3 by showing that it protects genome integrity during the 2-cell stage of mouse embryo development, in contrast to the previous functional assignment at postimplantation. This new role is mediated by a large, stable and hitherto overlooked deposit of maternal protein. Since protein abundance and stability defeat prospects of DNA- or RNA-based gene inactivation, we adopted a protein strategy of gene inactivation: antigen masking or TRIM21-mediated proteasomal degradation of COPS3. Both resulted in 2-cell embryo lethality, but the expected degradation remained outstanding, because the major fraction of the total COPS3 is secluded in a submembrane cortical rim that withstands extraction with detergent, thereby exposing a soluble vs. insoluble fraction of COPS3, which we ascribe with distinct functional properties. In mechanistic terms, transcriptomic and metabolic analyses reveal that soluble COPS3 is involved in several processes, which, however, converge on DNA endoreduplication and the accumulation of DNA strand breaks in the 2-cell nucleus, where the minor soluble fraction of COPS3 is placed. Thus, we have shown the critical role of maternal protein deposits in development, and we have also highlighted the distinction between the site of accumulation (cell cortex) and point of use (nucleus), which is a dimension of the protein-based strategies of gene inactivation not yet fully appreciated.

show abstract

Section: Discussionsupporting

confidence: 56%

Section: Discussionsupporting

confidence: 56%

A Critical Role for The COP9 Signalosome Subunit 3 as A Gatekeeper of Genome Integrity in 2-Cell Mouse Embryos

Israel

Drexler

Fuellen

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Conditional (B cell) Impaired B cell maturity and development 256 Conditional (T cell) Insufficiency of T cells 257 Conditional (oocyte) Oocyte death and infertility 69,70 Conditional (oocyte) Female infertility 68 Dcaf2 −/− Substrate recognition protein Germline Susceptible to UV-induced skin carcinogenesis 76 Abbreviations: MDSCs: myeloid-derived suppressor cells; LPS: lipopolysaccharide; UV: ultraviolet;…”

Section: Substrate Recognition Proteinmentioning

confidence: 99%

“…While female reproduction remains normal in individual Cul4a −/− mice, abrogation of the entire CRL4 ubiquitin ligase led to infertility in females 67 . Interestingly, conditional deletion of Ddb1 or CRL4 substrate receptors VprBP/DCAF1 or DCAF2 cause female infertility possibly via diverse mechanisms including, massive DNA damage and disruption of the cell cycle, TET (Ten-eleven translocation methylcytosine dioxygenase) inactivation-mediated ovulation defects, oocyte loss, or repression on PI3K/Akt pathway [68][69][70] .…”

Section: Introduction Of Cullin 4 E3 Ligasesmentioning

confidence: 99%

The emerging role for Cullin 4 family of E3 ligases in tumorigenesis

Cheng

Guo

North

et al. 2019

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

View full text Add to dashboard Cite

As a member of the Cullin-RING ligase family, Cullin-RING ligase 4 (CRL4) has drawn much attention due to its broad regulatory roles under physiological and pathological conditions, especially in neoplastic events. Based on evidence from knockout and transgenic mouse models, human clinical data, and biochemical interactions, we summarize the distinct roles of the CRL4 E3 ligase complexes in tumorigenesis, which appears to be tissue-and context-dependent. Notably, targeting CRL4 has recently emerged as a noval anti-cancer strategy, including thalidomide and its derivatives that bind to the substrate recognition receptor cereblon (CRBN), and anticancer sulfonamides that target DCAF15 to suppress the neoplastic proliferation of multiple myeloma and colorectal cancers, respectively. To this end, PROTACs have been developed as a group of engineered bi-functional chemical glues that induce the ubiquitinationmediated degradation of substrates via recruiting E3 ligases, such as CRL4 (CRBN) and CRL2 (pVHL). We summarize the recent major advances in the CRL4 research field towards understanding its involvement in tumorigenesis and further discuss its clinical implications. The anti-tumor effects using the PROTAC approach to target the degradation of undruggable targets are also highlighted.

show abstract

“…They are known as DDB1-associated and cullin-4-associated factors (DCAFs) [8]. The in vivo functions of oocyte-derived DCAF1 and DCAF2 in mediating oocyte meiosis and zygotic genome stability have been reported [9,10]. By RNA interference (RNAi) screening in Caenorhabditis elegans, we found that a novel DCAF conserved from Schizosaccharomyces pombe to Homo sapiens plays an important part in oogenesis.…”

Section: Introductionmentioning

confidence: 99%

Mammalian nucleolar protein DCAF13 is essential for ovarian follicle maintenance and oocyte growth by mediating rRNA processing

Zhang

Zhao

et al. 2018

Cell Death Differ

Self Cite

View full text Add to dashboard Cite

During mammalian oocyte growth, chromatin configuration transition from the nonsurrounded nucleolus (NSN) to surrounded nucleolus (SN) type plays a key role in the regulation of gene expression and acquisition of meiotic and developmental competence by the oocyte. Nonetheless, the mechanism underlying chromatin configuration maturation in oocytes is poorly understood. Here we show that nucleolar protein DCAF13 is an important component of the ribosomal RNA (rRNA)-processing complex and is essential for oocyte NSN-SN transition in mice. A conditional knockout of Dcaf13 in oocytes led to the arrest of oocyte development in the NSN configuration, follicular atresia, premature ovarian failure, and female sterility. The DCAF13 deficiency resulted in pre-rRNA accumulation in oocytes, whereas the total mRNA level was not altered. Further exploration showed that DCAF13 participated in the 18S rRNA processing in growing oocytes. The lack of 18S rRNA because of DCAF13 deletion caused a ribosome assembly disorder and then reduced global protein synthesis. DCAF13 interacted with a protein of the core box C/D ribonucleoprotein, fibrillarin, i.e., a factor of early pre-rRNA processing. When fibrillarin was knocked down in the oocytes from primary follicles, follicle development was inhibited as well, indicating that an rRNA processing defect in the oocyte indeed stunts chromatin configuration transition and follicle development. Taken together, these results elucidated the in vivo function of novel nucleolar protein DCAF13 in maintaining mammalian oogenesis.

show abstract

Maternal DCAF2 is crucial for maintenance of genome stability during the first cell cycle in mice

Cited by 19 publications

References 38 publications

A Critical Role for The COP9 Signalosome Subunit 3 as A Gatekeeper of Genome Integrity in 2-Cell Mouse Embryos

A Critical Role for The COP9 Signalosome Subunit 3 as A Gatekeeper of Genome Integrity in 2-Cell Mouse Embryos

The emerging role for Cullin 4 family of E3 ligases in tumorigenesis

Mammalian nucleolar protein DCAF13 is essential for ovarian follicle maintenance and oocyte growth by mediating rRNA processing

Contact Info

Product

Resources

About