Abstract
If fertilization does not occur for a prolonged time after ovulation, oocytes undergo a time-dependent deterioration in quality in vivo and in vitro, referred to as postovulatory aging. The DNA damage response is thought to decline with aging, but little is known about how mammalian oocytes respond to the DNA damage during in vitro postovulatory aging. Here we show that increased WIP1 during in vitro postovulatory aging suppresses the capacity of oocytes to respond to and repair DNA damage. During in vitro aging, oocytes progressively lost their capacity to respond to DNA double-strand breaks, which corresponded with an increase in WIP1 expression. Increased WIP1 impaired the amplification of γ-H2AX signaling, which reduced the DNA repair capacity. WIP1 inhibition restored the DNA repair capacity, which prevented deterioration in oocyte quality and improved the fertilization and developmental competence of aged oocytes. Importantly, WIP1 was also found to be high in maternally aged oocytes, and WIP1 inhibition enhanced the DNA repair capacity of maternally aged oocytes. Therefore, our results demonstrate that increased WIP1 is responsible for the age-related decline in DNA repair capacity in oocytes, and WIP1 inhibition could restore DNA repair capacity in aged oocytes.
Highlights
DNA double-strand breaks (DSBs) are often generated in genomic DNA during DNA replication or transcription or upon exposure to genotoxic agents such as ionizing radiation or chemicals
Our results suggest that the impaired DNA damage repair found in aged oocytes is a consequence of increased WIP1 levels, and FIGURE 4 | WIP1 inhibition promotes DNA damage repair in aged oocytes. (A–C) After treatment with etoposide (ETP) or dimethyl sulfoxide (DMSO) as a control (CTL), oocytes aged in vitro for 24 h were cultured in ETP-free medium for 1 h with GSK2830371 (GSK) or DMSO
No one yet understands why DNA damage accumulates with age or what molecular mechanism is responsible for the age-associated decline in DNA repair capacity
Summary
DNA double-strand breaks (DSBs) are often generated in genomic DNA during DNA replication or transcription or upon exposure to genotoxic agents such as ionizing radiation or chemicals. The phosphorylated tail of c-H2AX creates a docking platform for the mediator protein MDC1, which recruits additional ATM and MRN complexes to the vicinity of the DSB, thereby amplifying ATM recruitment and activation and spreading c-H2AX to adjacent chromatin (Stucki et al, 2005; Polo and Jackson, 2011; Panier and Boulton, 2014). This stepwise amplification of c-H2AX signaling ensures the repair of damaged DNA by stabilizing the broken ends and recruiting repair factors (Celeste et al, 2003)
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