DNA damage signals from somatic uterine tissue arrest oogenesis through activated DAF-16

Abstract

Germ line integrity is critical for progeny fitness. Organisms deploy the DNA damage response (DDR) signaling to protect the germ line from genotoxic stress, facilitating the cell-cycle arrest of germ cells and DNA repair or their apoptosis. Cell-autonomous regulation of germ line quality in response to DNA damage is well-studied; however, how quality is enforced cell non-autonomously on sensing somatic D NA damage is less known. Using Caenorhabditis elegans, we show that DDR disruption, only in the uterus, when insulin-IGF-1 signaling (IIS) is low, arrests oogenesis in the pachytene stage of meiosis I, in a FOXO/DAF-16 transcription factor (TF)-dependent manner. Without FOXO/DAF-16, germ cells of the IIS mutant escape the arrest to produce poor-quality oocytes, showing that the TF imposes strict quality control during low IIS. Activated FOXO/DAF-16 senses DDR perturbations during low IIS to lower ERK/MPK-1 signaling below a threshold to promote germ line arrest. Altogether, we elucidate a new surveillance role of activated FOXO/DAF-16 that ensures optimal germ cell quality and progeny fitness in response to somatic DNA damage.

A non-canonical role of somatic CYCLIN D/CYD-1 in oogenesis and reproductive aging, dependent on the FOXO/DAF-16 activation state

“…In a recent study, we described the crosstalk of the cyclin-dependent protein kinase, cdk-12 with the IIS pathway to regulate germ cell development (Sarkar et al, 2023). Interestingly, in that study, the function of the cdk-12 was found to be independent of its canonical cyclin, cyclin K/ccnk-1 (Blazek et al, 2011).…”

“…In line with this, we also find that cyd-1 regulates oocyte quality and pachytene arrest of the germ cells, cell non-autonomously from the somatic gonad (uterus) under wild-type and low IIS, respectively ( Figure 7 ) . We have previously demonstrated that somatic DNA damage triggers DAF-16/FOXO-dependent stalling of oogenesis under low IIS in a cell non-autonomous manner (Sarkar et al, 2023). In a different context, somatic ERK/MPK-1 (Robinson-Thiewes et al, 2021) and kri-1 (Ito et al, 2010) have been shown to influence germ cell proliferation and death, respectively.…”

“…The role of FOXO proteins has been well documented as a checkpoint, where in various cell line models it orchestrates cell-cycle arrest and repair in response to DNA damage and oxidative stress (Furukawa-Hibi et al, 2002;Hill et al, 2014;Hornsveld et al, 2021;Tran et al, 2002). We have earlier shown that DAF-16 responds to somatic DNA damage and arrests germline to protect the progeny (Sarkar et al, 2023). Also, on sensing the unavailability of food, newly hatched worms utilize DAF-16 to arrest at the L1 diapause stage and resume development upon re-feeding (Baugh and Sternberg, 2006;Jensen et al, 2006).…”

“…To identify unexplored interactors of the IIS pathway, we had earlier performed a reverse genetic screen and identified a cyclin-dependent kinase CDK-12 that regulates oogenesis cell non-autonomously (Sarkar et al, 2023). To broaden our understanding of other cell cycle regulators that may have non-canonical roles in aging and if they crosstalk with the IIS pathway, we screened for cyclins that regulate germline development.…”

Kinome-wide RNAi screen inCaenorhabditis elegansreveals new modulators of insulin signaling and longevity

“…In this direction, our recent study with one such identified kinase hit, B0285.1/CDK-12, shows that it is crucial for maintaining DNA integrity. We used CDK-12 as a genetic tool to analyze the effects of tissue-specific DDR perturbation and DNA damage in the IIS pathway mutants 56 . We found that knocking down cdk-12 only in the somatic uterine tissue of the IIS pathway mutants led to a DAF-16-dependent pachytene arrest of germ cells.…”