Stella preserves maternal chromosome integrity by inhibiting 5hmC‐induced γH2 AX accumulation

Abstract

In the mouse zygote, Stella/PGC7 protects 5-methylcytosine (5mC) of the maternal genome from Tet3-mediated oxidation to 5-hydroxymethylcytosine (5hmC). Although ablation of Stella causes early embryonic lethality, the underlying molecular mechanisms remain unknown. In this study, we report impaired DNA replication and abnormal chromosome segregation (ACS) of maternal chromosomes in Stella-null embryos. In addition, phosphorylation of H2AX (cH2AX), which has been reported to inhibit DNA replication, accumulates in the maternal chromatin of Stella-null zygotes in a Tet3-dependent manner. Cell culture assays verified that ectopic appearance of 5hmC induces abnormal accumulation of cH2AX and subsequent growth retardation. Thus, Stella protects maternal chromosomes from aberrant epigenetic modifications to ensure early embryogenesis.

TET2-mediated 5-hydroxymethylcytosine induces genetic instability and mutagenesis

“…We speculate that these complexes may favor chromosomal instability. In agreement with our data, recent work by Nakatani et al reported an impaired DNA replication and abnormal segregation of maternal chromosomes in Stella −/− embryos in a Tet3-dependent manner [38]. However, at physiological levels, 5-hmC were reported to prevent chromosome missegregation after stress replication [36].…”

Alternative roles for oxidized mCs and TETs

“…Accumulation of γH2AX also occurs in the absence of DSBs to regulate cell cycle progression by inhibiting DNA replication [68,69]. In this context the overexpression of TET proteins in NIH-3T3 cells has been shown to induce 5hmC, accumulate γH2AX and delay DNA replication [70]. Given that genomic stability relies on DNA replication fidelity during S phase and correct segregation of sister chromatids during mitosis, the role of oxi-mCs in these highly coordinated cellular processes should be investigated further.…”

SUV4-20 activity in the preimplantation mouse embryo controls timely replication

“…4G). Since longer inhibition of ATR is known to block developmental progression (Brown and Baltimore 2000;Nakatani et al 2015), we focused specifically on assessing the developmental block beyond the two-cell stage, which accounts for the majority of the phenotype (77% of SUV4-20H2 embryos arrest prior to the two-cell stage), by scoring embryos that reached the four-toeight-cell stage transition. As shown in Figure 4G, all noninjected embryos cultured in the presence of the ATRi reached the four-cell stage at a rate similar to that of noninjected embryos cultured without inhibitor.…”