Loss of Emi1-dependent Anaphase-promoting Complex/cyclosome Inhibition Deregulates E2F Target Expression and Elicits DNA Damage-induced Senescence

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2007 Sep 19

PMID 17875940

Citations 24

Authors

Emmy W Verschuren

Kenneth H Ban

Marilyn A Masek

Norman L Lehman

Peter K Jackson

Affiliations

Soon will be listed here.

Abstract

Expression of the anaphase-promoting complex/cyclosome (APC/C) inhibitor Emi1 is required for the accumulation of APC/C substrates crucial for DNA synthesis and mitotic entry. We show that in vivo Emi1 expression correlates with the proliferative status of the cellular compartment and that cells lacking Emi1 undergo cellular senescence. Emi1 depletion leads to strong decreases in E2F target mRNA and APC/C substrate protein abundances. However, cyclin E mRNA and cyclin E protein levels and associated kinase activities are increased. Cells lacking Emi1 undergo DNA damage, likely explained by replication stress upon deregulated cyclin E- and A-associated kinase activities. Inhibition of ATM kinase prevents induction of senescence, implying that senescence is a consequence of DNA damage. Surprisingly, no senescence or no extensive amount of senescence is evident upon depletion of the Emi1-stabilizing factor Evi5 or Pin1, respectively. Our data suggest that maintenance of a protein stabilization/mRNA expression positive-feedback circuit fueled by Emi1 is required for accurate cell cycle progression, maintenance of DNA integrity, and prevention of cellular senescence.

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