ABSTRACT
Precise regulation of DNA replication and genome integrity is crucial for gametogenesis and early embryogenesis. Cullin ring-finger ubiquitin ligase 4 (CRL4) has multiple functions in the maintenance of germ cell survival, oocyte meiotic maturation, and maternal-zygotic transition in mammals. DDB1–cullin-4-associated factor-2 (DCAF2, also known as DTL or CDT2) is an evolutionarily conserved substrate receptor of CRL4. To determine whether DCAF2 is a key CRL4 substrate adaptor in mammalian oocytes, we generated a novel mouse strain that carries a Dcaf2 allele flanked by loxP sequences, and specifically deleted Dcaf2 in oocytes. Dcaf2 knockout in mouse oocytes leads to female infertility. Although Dcaf2-null oocytes were able to develop and mature normally, the embryos derived from them were arrested at one- to two-cell stage, owing to prolonged DNA replication and accumulation of massive DNA damage. These results indicate that DCAF2 is a previously unrecognized maternal factor that safeguards zygotic genome stability. Maternal DCAF2 protein is crucial for prevention of DNA re-replication in the first and unique mitotic cell cycle of the zygote.
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Footnotes
Author contributions
Conceptualization: H.-Y.F.; Methodology: X.W.; Investigation: Y.-W.X., L.-R.C., M.W.; Resources: Y.X.; Data curation: H.-Y.F.; Writing - original draft: Y.-W.X.; Writing - review & editing: C.T., H.-Y.F.; Supervision: J.L., H.-Y.F.; Funding acquisition: J.L., C.T., H.-Y.F.
Funding
This work was supported by the National Key Research and Development Program of China (2016YFC1000600, 2017YFSF1001500 and 2017YFC1001100) and National Natural Science Foundation of China (31528016, 31371449 and 31671558).
