Loss of cep57 function induces G1 arrest and microcephaly

Centrosome is a key cell signaling hub, orchestrating mitotic events and the distribution of cell fate determinants. Centrosomal dysfunction results in mitotic aberrations such as microtubule disorganization, mitotic spindle anomalies, and orientation defects, leading to cell division errors. Yet, how centrosomal defects are communicated to cell cycle checkpoints during embryogenesis remains unresolved. Centrosomal protein 57 (CEP57) is best known for its role in centrosome organization, where it regulates microtubule nucleation, stabilization, and spindle assembly. Here, we uncover previously undescribed, distinct functions of Cep57 in regulating G1/S progression, centrosome integrity, and DNA damage responses during early embryogenesis. In early zebrafish embryos, Cep57 localizes to both the nucleus and centrosomes, suggesting dual roles in cytoskeletal organization and nuclear cell cycle regulation. Cep57 interacts with Rad21, and its loss results in consequential depletion of Rad21, leading to supernumerary nuclei and defects in pericentriolar material organization. Our results also show that Cep57 interacts with Geminin, and it induces an Rb1-dependent G1 arrest. Hence, lack of Cep57 results in widespread cell cycle defects, genome instability, and increased apoptosis. Quantitative proteomics reveals induction of DNA damage responses and checkpoint pathways, indicating engagement of genome surveillance programs downstream of centrosome dysfunction. Thus, we show that Cep57 functions as a molecular bridge linking centrosome integrity to G1/S checkpoint control in early embryos. These cellular defects precede and likely underlie neural tissue apoptosis and microcephaly-associated characteristics observed in Cep57-deficient embryos. Together, our findings identify Cep57 as a critical integrator of centrosome organization, cell cycle progression, and genome stability, expanding its functional scope beyond canonical centrosome regulation during vertebrate embryogenesis.