TY - JOUR

T1 - The RIF1-PP1 Axis Controls Abscission Timing in Human Cells

AU - Bhowmick, Rahul

AU - Thakur, Roshan Singh

AU - Venegas, Andrés Bueno

AU - Liu, Ying

AU - Nilsson, Jakob

AU - Barisic, Marin

AU - Hickson, Ian D

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

U2 - 10.1016/j.cub.2019.02.037

DO - 10.1016/j.cub.2019.02.037

M3 - Journal article

C2 - 30905608

VL - 29

SP - 1232-1242.e5

JO - Current Biology

JF - Current Biology

SN - 0960-9822

IS - 7

ER -