Loss of cep57 function induces G1 arrest and microcephaly

Abstract

Faithful chromosome segregation and coordinated cell-cycle progression are essential for maintaining genome stability and preserving progenitor populations during vertebrate embryogenesis. Although pathogenic CEP57 variants are associated with developmental disorders including aneuploidy and microcephaly, the molecular mechanisms by which CEP57 coordinates these processes remain poorly understood. Here, we identify Cep57 as a previously unrecognized regulator of chromosome segregation, G1/S transition, centrosome integrity, and genome surveillance during early zebrafish embryogenesis. Cep57 localizes to both the nucleus and centrosomes of zebrafish blastulae, indicating probable dual functions in nuclear cell cycle regulation and centrosome organization. Our results show that Cep57 associates with Rad21, Smc1, and Smc3, revealing an unexpected functional link between Cep57 and the cohesin complex. Loss of Cep57 results in Rad21 depletion, destabilization of the cohesin complex, chromosome segregation errors resulting in supernumerary nuclei, and disruption of pericentriolar material organization, demonstrating a critical role in maintaining mitotic fidelity. We further show that Cep57 interacts with Geminin and promotes an Rb1-dependent G1/S checkpoint, whereas Cep57 deficiency causes widespread cell cycle dysregulation, genome instability, and apoptosis. Quantitative proteomic analyses reveal robust activation of DNA damage and checkpoint signaling pathways, consistent with engagement of genome surveillance mechanisms following Cep57 loss. Importantly, these cellular abnormalities precede extensive neural apoptosis, depletion of neuroprogenitor populations, and the emergence of microcephaly-associated phenotypes. Collectively, our findings establish Cep57 as a cohesin-associated integrator of chromosome segregation, cell cycle progression, and genome stability that is essential for neural progenitor maintenance during vertebrate embryogenesis, thereby expanding its functional repertoire far beyond its canonical role in centrosome regulation.