The RIF1-PP1 Axis Controls Abscission Timing in Human Cells

Rahul Bhowmick; Roshan Singh Thakur; Andrés Bueno Venegas; Ying Liu; Jakob Nilsson; Marin Barisic; Ian D Hickson

doi:10.1016/j.cub.2019.02.037

The RIF1-PP1 Axis Controls Abscission Timing in Human Cells

Rahul Bhowmick, Roshan Singh Thakur, Andrés Bueno Venegas, Ying Liu, Jakob Nilsson, Marin Barisic, Ian D Hickson

12 Citations (Scopus)

Abstract

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. 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.

Original language	English
Journal	Current Biology
Volume	29
Issue number	7
Pages (from-to)	1232-1242.e5
ISSN	0960-9822
DOIs	https://doi.org/10.1016/j.cub.2019.02.037
Publication status	Published - 1 Apr 2019

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cub.2019.02.037

http://www.cell.com/article/S0960982219302076/pdf

Cite this

@article{b76da843d2264663bb473043d3d0afbe,

title = "The RIF1-PP1 Axis Controls Abscission Timing in Human Cells",

abstract = "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. 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.",

author = "Rahul Bhowmick and Thakur, {Roshan Singh} and Venegas, {Andr{\'e}s Bueno} and Ying Liu and Jakob Nilsson and Marin Barisic and Hickson, {Ian D}",

year = "2019",

month = apr,

day = "1",

doi = "10.1016/j.cub.2019.02.037",

language = "English",

volume = "29",

pages = "1232--1242.e5",

journal = "Current Biology",

issn = "0960-9822",

publisher = "Cell Press",

number = "7",

}

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 - 2019/4/1

Y1 - 2019/4/1

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. 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.

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. 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.

U2 - 10.1016/j.cub.2019.02.037

DO - 10.1016/j.cub.2019.02.037

M3 - Journal article

C2 - 30905608

SN - 0960-9822

VL - 29

SP - 1232-1242.e5

JO - Current Biology

JF - Current Biology

IS - 7

ER -

The RIF1-PP1 Axis Controls Abscission Timing in Human Cells

Abstract

UN SDGs

Access to Document

Fingerprint

Cite this