Polycomb proteins control proliferation and transformation independently of cell cycle checkpoints by regulating DNA replication

Andrea Piunti; Alessandra Rossi; Aurora Cerutti; Mareike Albert; Sriganesh Jammula; Andrea Scelfo; Laura Cedrone; Giulia Fragola; Linda Elin Pålsson; Haruhiko Koseki; Giuseppe Testa; Stefano Casola; Kristian Helin; Fabrizio d'Adda di Fagagna; Diego Pasini

doi:10.1038/ncomms4649

Polycomb proteins control proliferation and transformation independently of cell cycle checkpoints by regulating DNA replication

Andrea Piunti, Alessandra Rossi, Aurora Cerutti, Mareike Albert, Sriganesh Jammula, Andrea Scelfo, Laura Cedrone, Giulia Fragola, Linda Elin Pålsson, Haruhiko Koseki, Giuseppe Testa, Stefano Casola, Kristian Helin, Fabrizio d'Adda di Fagagna, Diego Pasini

The Danish Stem Cell Center

56 Citations (Scopus)

Abstract

The ability of PRC1 and PRC2 to promote proliferation is a main feature that links polycomb (PcG) activity to cancer. PcGs silence the expression of the tumour suppressor locus Ink4a/Arf, whose products positively regulate pRb and p53 functions. Enhanced PcG activity is a frequent feature of human tumours, and PcG inhibition has been proposed as a strategy for cancer treatment. However, the recurrent inactivation of pRb/p53 responses in human cancers raises a question regarding the ability of PcG proteins to affect cellular proliferation independently from this checkpoint. Here we demonstrate that PRCs regulate cellular proliferation and transformation independently of the Ink4a/Arf-pRb-p53 pathway. We provide evidence that PRCs localize at replication forks, and that loss of their function directly affects the progression and symmetry of DNA replication forks. Thus, we have identified a novel activity by which PcGs can regulate cell proliferation independently of major cell cycle restriction checkpoints.

Original language	English
Journal	Nature Communications
Volume	5
Pages (from-to)	3649
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms4649
Publication status	Published - 14 Apr 2014

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Piunti, A., Rossi, A., Cerutti, A., Albert, M., Jammula, S., Scelfo, A., Cedrone, L., Fragola, G., Pålsson, L. E., Koseki, H., Testa, G., Casola, S., Helin, K., d'Adda di Fagagna, F., & Pasini, D. (2014). Polycomb proteins control proliferation and transformation independently of cell cycle checkpoints by regulating DNA replication. Nature Communications, 5, 3649. https://doi.org/10.1038/ncomms4649

Piunti, A, Rossi, A, Cerutti, A, Albert, M, Jammula, S, Scelfo, A, Cedrone, L, Fragola, G, Pålsson, LE, Koseki, H, Testa, G, Casola, S, Helin, K, d'Adda di Fagagna, F & Pasini, D 2014, 'Polycomb proteins control proliferation and transformation independently of cell cycle checkpoints by regulating DNA replication', Nature Communications, vol. 5, pp. 3649. https://doi.org/10.1038/ncomms4649

@article{6275be378759479392cd84cfc28cacd4,

title = "Polycomb proteins control proliferation and transformation independently of cell cycle checkpoints by regulating DNA replication",

abstract = "The ability of PRC1 and PRC2 to promote proliferation is a main feature that links polycomb (PcG) activity to cancer. PcGs silence the expression of the tumour suppressor locus Ink4a/Arf, whose products positively regulate pRb and p53 functions. Enhanced PcG activity is a frequent feature of human tumours, and PcG inhibition has been proposed as a strategy for cancer treatment. However, the recurrent inactivation of pRb/p53 responses in human cancers raises a question regarding the ability of PcG proteins to affect cellular proliferation independently from this checkpoint. Here we demonstrate that PRCs regulate cellular proliferation and transformation independently of the Ink4a/Arf-pRb-p53 pathway. We provide evidence that PRCs localize at replication forks, and that loss of their function directly affects the progression and symmetry of DNA replication forks. Thus, we have identified a novel activity by which PcGs can regulate cell proliferation independently of major cell cycle restriction checkpoints.",

author = "Andrea Piunti and Alessandra Rossi and Aurora Cerutti and Mareike Albert and Sriganesh Jammula and Andrea Scelfo and Laura Cedrone and Giulia Fragola and P{\aa}lsson, {Linda Elin} and Haruhiko Koseki and Giuseppe Testa and Stefano Casola and Kristian Helin and {d'Adda di Fagagna}, Fabrizio and Diego Pasini",

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T1 - Polycomb proteins control proliferation and transformation independently of cell cycle checkpoints by regulating DNA replication

AU - Piunti, Andrea

AU - Rossi, Alessandra

AU - Cerutti, Aurora

AU - Albert, Mareike

AU - Jammula, Sriganesh

AU - Scelfo, Andrea

AU - Cedrone, Laura

AU - Fragola, Giulia

AU - Pålsson, Linda Elin

AU - Koseki, Haruhiko

AU - Testa, Giuseppe

AU - Casola, Stefano

AU - Helin, Kristian

AU - d'Adda di Fagagna, Fabrizio

AU - Pasini, Diego

PY - 2014/4/14

Y1 - 2014/4/14

N2 - The ability of PRC1 and PRC2 to promote proliferation is a main feature that links polycomb (PcG) activity to cancer. PcGs silence the expression of the tumour suppressor locus Ink4a/Arf, whose products positively regulate pRb and p53 functions. Enhanced PcG activity is a frequent feature of human tumours, and PcG inhibition has been proposed as a strategy for cancer treatment. However, the recurrent inactivation of pRb/p53 responses in human cancers raises a question regarding the ability of PcG proteins to affect cellular proliferation independently from this checkpoint. Here we demonstrate that PRCs regulate cellular proliferation and transformation independently of the Ink4a/Arf-pRb-p53 pathway. We provide evidence that PRCs localize at replication forks, and that loss of their function directly affects the progression and symmetry of DNA replication forks. Thus, we have identified a novel activity by which PcGs can regulate cell proliferation independently of major cell cycle restriction checkpoints.

AB - The ability of PRC1 and PRC2 to promote proliferation is a main feature that links polycomb (PcG) activity to cancer. PcGs silence the expression of the tumour suppressor locus Ink4a/Arf, whose products positively regulate pRb and p53 functions. Enhanced PcG activity is a frequent feature of human tumours, and PcG inhibition has been proposed as a strategy for cancer treatment. However, the recurrent inactivation of pRb/p53 responses in human cancers raises a question regarding the ability of PcG proteins to affect cellular proliferation independently from this checkpoint. Here we demonstrate that PRCs regulate cellular proliferation and transformation independently of the Ink4a/Arf-pRb-p53 pathway. We provide evidence that PRCs localize at replication forks, and that loss of their function directly affects the progression and symmetry of DNA replication forks. Thus, we have identified a novel activity by which PcGs can regulate cell proliferation independently of major cell cycle restriction checkpoints.

U2 - 10.1038/ncomms4649

DO - 10.1038/ncomms4649

M3 - Journal article

C2 - 24728135

SN - 2041-1723

VL - 5

SP - 3649

JO - Nature Communications

JF - Nature Communications

ER -

Polycomb proteins control proliferation and transformation independently of cell cycle checkpoints by regulating DNA replication

Abstract

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