The RIF1-PP1 Axis Controls Abscission Timing in Human Cells

• Published in: Current biology 2019-04, Vol.29 (7), p.1232-1242.e5
• Main Authors: Bhowmick, Rahul, Thakur, Roshan Singh, Venegas, Andrés Bueno, Liu, Ying, Nilsson, Jakob, Barisic, Marin, Hickson, Ian D.
• Format: Article
• Language: English
• Subjects: Aurora B; CHMP4C; cytokinesis; Cytokinesis - physiology; Humans; mitosis; Mitosis - genetics; Mitosis - physiology; protein phosphatases; Receptors, Neuropeptide Y - genetics; Receptors, Neuropeptide Y - metabolism; Telomere-Binding Proteins - genetics; Telomere-Binding Proteins - metabolism; ultrafine DNA bridges
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2019.02.037

Abscission is the final step of cell division when the cytokinetic furrow ingresses completely, leading to midbody formation and plasma membrane fission [1]. In human cells, the Aurora-B-driven abscission checkpoint delays cytokinesis until any residual chromatin spanning the midbody is removed [2–5]. If this does not occur efficiently, uneven segregation of daughter genomes can occur. The mechanism by which the abscission checkpoint becomes satisfied to permit cytokinesis is poorly defined. Here, we identify RIF1 and its binding partner, protein phosphatase 1 (PP1), as being critical for regulation of abscission timing in human cells. We show that RIF1 promotes cytokinesis through recruitment of PP1 to the midbody, which then counteracts Aurora B kinase activity, leading to dephosphorylation of a regulator of abscission timing, CHMP4C [6–10]. Although RIF1 binds to unresolved DNA bridges that persist into telophase [11], we show that this cytokinetic function of the RIF1-PP1 axis is not limited to instances where cell division is perturbed by the presence of bridges. Nevertheless, we show that altering the balance of the opposing Aurora B kinase and PP1 phosphatase activities makes cells unresponsive to DNA bridges and sensitizes cells to agents that induce bridge formation. Our data define a new mechanism for regulation of abscission timing and emphasize how antagonism between kinases and phosphatases is a widespread mechanism for determining the timing of mitotic transactions. Because cancer cells experiencing oncogene-induced replication stress generate excessive mitotic DNA bridging [12], targeting this new regulatory pathway could be a promising therapeutic strategy. [Display omitted] •Ultrafine anaphase bridges (UFBs) activate the abscission checkpoint in human cells•The UFB binding protein RIF1 targets protein phosphatase 1 (PP1) to the midbody•PP1 counteracts the Aurora-B-kinase-driven checkpoint by targeting CHMP4C•The RIF1/PP1 axis regulates abscission timing Bhowmick et al. have uncovered the mechanism by which the Aurora-B-kinase-driven abscission checkpoint is satisfied to allow cytokinesis in human cells. The DNA repair protein RIF1 localizes to and targets protein phosphatase 1 (PP1) to the midbody. PP1 then counteracts Aurora B to promote abscission.