Senescence is an irreversible proliferation withdrawal that can be initiated after DNA damage-induced cell cycle arrest in G2 phase to prevent genomic instability. Senescence onset in G2 requires p53 and RB family tumour suppressors, but how they are regulated to convert a temporary cell cycle arrest into a permanent one remains unknown. Here, we show that a previously unrecognised balance between the CDK inhibitor p21 and Chk1 controls D-type cyclin-CDK activity during G2 arrest. In non-transformed cells, p21 activates RB in G2 by inhibiting Cyclin D1-CDK2/CDK4. The resulting G2 exit, which precedes appearance of senescence markers, is associated with a mitotic bypass, Chk1 downregulation and DNA damage foci reduction. In p53/RB-proficient cancer cells, compromised G2 exit correlates with sustained Chk1 activity, delayed p21 induction, untimely Cyclin E1 re-expression and genome reduplication. Conversely, Chk1 depletion promotes senescence by inducing p21 binding to Cyclin D1 and Cyclin E1-CDK complexes and down-regulating CDK6, whereas Chk2 knockdown enables RB phosphorylation and delays G2 exit. In conclusion, p21 and Chk2 oppose Chk1 to maintain RB activity, thus promoting DNA damage-induced senescence onset in G2.
Reciprocal regulation of p21 and Chk1 controls the Cyclin D1-RB pathway to mediate senescence onset after G2 arrest
These authors contributed equally to this work
Present address: Institut du cancer de Montpellier, Montpellier, France
Present address: Stanford University School of Medicine, Stanford, USA
Present address: PerkinElmer, Inc., Parc Marcel Boiteux, BP 84175 30200 Codolet, France
- Award Group:
- Funder(s): Association pour la Recherche sur le Cancer
- Award Id(s): 3793
- Funder(s):
- Award Group:
- Funder(s): Ligue Contre le Cancer
- Award Id(s): EL2013.LNCC/DF
- Funder(s):
- Award Group:
- Funder(s): Croatian Science Foundation
- Award Id(s): IP-2013-11-1615
- Funder(s):
- Award Group:
- Funder(s): Institut National Du Cancer
- Award Id(s): 2017-169
- Funder(s):
Currently Viewing Accepted Manuscript - Newer Version Available
Gerald Lossaint, Anđela Horvat, Véronique Gire, Katarina Bacevic, Karim Mrouj, Fabienne Charrier-Savournin, Virginie Georget, Daniel Fisher, Vjekoslav Dulic; Reciprocal regulation of p21 and Chk1 controls the Cyclin D1-RB pathway to mediate senescence onset after G2 arrest. J Cell Sci 2022; jcs.259114. doi: https://doi.org/10.1242/jcs.259114
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