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Preprint WatchMildOctober 19th, 2026

Stage-specific checkpoint signalling by ATM, ATR and DNA-PK safeguards oocyte genome integrity

Sioutas, G.; Perry, M. J.; Zielinska, A. P.; Elinati, E.; Fallesen, T.; Dao, V.; Ojarikre, O.; Turner, J.

ATR mediates meiotic surveillance in mouse oocytes, ATR removal rescues oocyte loss from asynapsis and persistent meiotic double-strand breaks, and a PIKK-independent route of oocyte elimination also operates.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

The preprint reports that ATR mediates meiotic surveillance in mouse oocytes, that removing ATR rescues oocyte loss in response to asynapsis and to persistent meiotic double-strand breaks, and that oocyte elimination also proceeds through a PIKK-independent route. The mechanistic claim concerns ovarian reserve rather than oncology. One ATR program is on file in the Claidex graph, a Phase 1 discontinuation in advanced solid tumours, ceralasertib-atr-advanced-solid-tumours-phase1-programme-discontinuation, recorded as a strategic reprioritisation rather than an efficacy or safety failure. The cross-reference is weak on indication overlap and is flagged at MILD for that reason. It remains worth logging because the paper identifies a tissue-specific consequence of ATR loss that clinical ATR inhibitor programs do not routinely measure.

Abstract excerpt

In somatic cells, DNA double-strand breaks (DSBs) are potentially catastrophic lesions that activate phosphatidylinositol 3-kinase-related kinase (PIKK) signalling to promote DNA repair or eliminate damaged cells. During meiosis, however, DSBs are deliberately generated as essential intermediates in homologous recombination, raising the question of how DNA damage signalling distinguishes programmed recombination from genome instability. To define how PIKK signalling is adapted to these distinct contexts, we resolved the function of the three PIKKs ATM, ATR and DNA-PK in physiological meiotic recombination and the response to postnatal DNA damage in mouse oocytes. Following postnatal irradiation, ATM functions as the dominant response kinase, with ATR and DNA-PK acting redundantly to eliminate damaged oocytes. In contrast, meiotic surveillance is mediated by ATR, with ATR removal rescuing oocyte loss in response to asynapsis and, independently, to persistent meiotic DSBs. Unexpectedly, depletion of ATR fails to rescue constitutive Atm-null oocytes, while co-depletion of ATR and DNA-PK results in only partial rescue, revealing a PIKK-independent mechanism of oocyte elimination. Our findings demonstrate that DNA damage signalling is developmentally reconfigured during oogenesis and highlight distinct pathways of oocyte elimination that may ultimately inform strategies to maintain the ovarian reserve in mammals.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.