Heldt2018 - Proliferation-quiescence decision in response to DNA damage

Heldt2018 - Proliferation-quiescence decision
in response to DNA damage

This model is described in the article:

A comprehensive model for
the proliferation-quiescence decision in response to endogenous
DNA damage in human cells.

Heldt FS, Barr AR, Cooper S, Bakal
C, Novák B.
Proc. Natl. Acad. Sci. U.S.A. 2018 Feb;
:
Abstract:

Human cells that suffer mild DNA damage can enter a
reversible state of growth arrest known as quiescence. This
decision to temporarily exit the cell cycle is essential to
prevent the propagation of mutations, and most cancer cells
harbor defects in the underlying control system. Here we
present a mechanistic mathematical model to study the
proliferation-quiescence decision in nontransformed human
cells. We show that two bistable switches, the restriction
point (RP) and the G1/S transition, mediate this decision by
integrating DNA damage and mitogen signals. In particular, our
data suggest that the cyclin-dependent kinase inhibitor p21
(Cip1/Waf1), which is expressed in response to DNA damage,
promotes quiescence by blocking positive feedback loops that
facilitate G1 progression downstream of serum stimulation.
Intriguingly, cells exploit bistability in the RP to convert
graded p21 and mitogen signals into an all-or-nothing
cell-cycle response. The same mechanism creates a window of
opportunity where G1 cells that have passed the RP can revert
to quiescence if exposed to DNA damage. We present experimental
evidence that cells gradually lose this ability to revert to
quiescence as they progress through G1 and that the onset of
rapid p21 degradation at the G1/S transition prevents this
response altogether, insulating S phase from mild, endogenous
DNA damage. Thus, two bistable switches conspire in the early
cell cycle to provide both sensitivity and robustness to
external stimuli.

This model is hosted on
BioModels Database
and identified by:
MODEL1703030000.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.

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