Signaling to TRP53 and TAp63 from CHK1/CHK2 is responsible for elimination of most oocytes defective for either chromosome synapsis or recombination

Abstract

Eukaryotic organisms have evolved mechanisms to prevent the accumulation of cells bearing genetic aberrations. This is especially crucial for the germline, because fecundity, and fitness of progeny would be adversely affected by an excessively high mutational incidence. The process of meiosis poses unique problems for mutation avoidance, due to the requirement for SPO11-induced programmed double strand breaks (DSBs) in recombination-driven pairing and segregation of homologous chromosomes. Mouse meiocytes bearing unrepaired meiotic DSBs or unsynapsed chromosomes are eliminated before completing meiotic prophase I. In previous work, we showed that checkpoint kinase 2 (CHK2; CHEK2), a canonical DNA damage response protein, is crucial for eliminating not only oocytes defective in meiotic DSB repair (e.g. Trip13 Gt mutants), but also asynaptic Spo11 -/oocytes that accumulate a threshold level of spontaneous DSBs. However, rescue of such oocytes by Chk2 deficiency was incomplete, raising the possibility that a parallel checkpoint pathway(s) exists. Here, we show that mouse oocytes lacking both TAp63 and TRP53 protects nearly all Spo11 -/and Trip13 Gt/Gt oocytes from elimination. We present evidence that checkpoint kinase I (CHK1; CHEK1), which is known to signal to TRP53, also becomes activated by persistent DSBs in oocytes, and to an increased degree when CHK2 is absent. The combined data indicate that nearly all oocytes reaching a threshold level of unrepaired DSBs are eliminated by a semi-redundant pathway of CHK1/CHK2 signaling to TRP53/TAp63.

Brooding Temperature Alters Yolk Sac Absorption and Affected Ovarian Development in Goslings

“…After silencing CDK1 and CHK1 genes [ 10 ], ovarian cell proliferation was inhibited and the apoptosis rate was increased. It is reported that CHK1 was crucial for eliminating the defective nature of oocyte during its meiotic phase [ 33 ]. The CHK1 and CHK2 dependent DNA damage response controls the number of oocytes [ 34 ].…”

The future of fertility preservation for women treated with chemotherapy

“…Ataxia-telangiectasia and Rad3-related (ATR) and checkpoint kinase 2 (CHK2) are both serinethreonine kinases that have important roles in the DNA damage response. Following induction of DNA damage, ATR activates CHK2 which, in turn, can activate TAp63 and trigger apoptosis within oocytes (Rinaldi et al, 2019). It has been shown that CHK2 deficient mice are resistant to irradiation-induced oocyte loss in mice, and in vitro inhibition of either CHK2 or CK1 is able to block oocytes from TAp63-mediated apoptosis caused by radiation, cisplatin, cyclophosphamide, or doxorubicin (Kim et al, 2013;Tuppi et al, 2018;Luan et al, 2019;Rinaldi et al, 2019).…”

“…Following induction of DNA damage, ATR activates CHK2 which, in turn, can activate TAp63 and trigger apoptosis within oocytes (Rinaldi et al, 2019). It has been shown that CHK2 deficient mice are resistant to irradiation-induced oocyte loss in mice, and in vitro inhibition of either CHK2 or CK1 is able to block oocytes from TAp63-mediated apoptosis caused by radiation, cisplatin, cyclophosphamide, or doxorubicin (Kim et al, 2013;Tuppi et al, 2018;Luan et al, 2019;Rinaldi et al, 2019). CK2II (a CHK2 inhibitor) and ETP46464 (an ATR inhibitor) were both able to prevent primordial follicle apoptosis in cultured mouse ovaries in vitro from 4-hydroxyperoxycyclophophamide, a cyclophosphamide metabolite (Luan et al, 2019).…”