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hong1

hong1

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Reactions

r1

r1

∅ > M

r10

r10

∅ > TF + CP2

r11

r11

CP2 > ∅

r12

r12

TF + CP2 > ∅

r13

r13

CP2 > ∅

r14

r14

CP2 > ∅

r15

r15

∅ > TF

r16

r16

∅ > TF

r17

r17

∅ > TF

r2

r2

∅ > M

r3

r3

M > ∅

r4

r4

∅ > CP

r5

r5

CP > ∅

r6

r6

{2.0}CP > CP2

r7

r7

CP2 > {2.0}CP

r8

r8

CP > ∅

r9

r9

CP > ∅

Parameters

Global parameters

Fixed species

Initial values

Functions and Rules

Assignment rules

IC = TFtot - TF

function_1 = kcps * M

function_4_r17 = kp2 * IC / (Jp + CP + 2.0 * CP2 + 2.0 * IC) / system

function_4_r2 = kms * pow(TF, n) / (pow(J, n) + pow(TF, n)) / system

chk2pulseonoff = chk2pulseactive - (chk2pulseactive_elim_elim + chk2pulseactive_elim)

function_4_r8 = kp1 * CP / (Jp + CP + 2.0 * CP2 + 2.0 * IC) / system

function_4_r13 = kp2 * CP2 / (Jp + CP + 2.0 * CP2 + 2.0 * IC) / system

function_4_r1 = Dex / system

CPtot = CP + 2.0 * CP2 + 2.0 * IC

trigOFFtime = trigONtime + IR_pulse_duration

chk2c = chk2ToggleOnOff*(chk2pulseonoff * (chk2c_value / IR_pulse_duration))

chk2 = chk2ToggleOnOff*(chk2pulseonoff * (chk2_value / IR_pulse_duration))

Function definitions

Events

trigON

Trigger: geq(time, trigONtime)

Delay: 0

Assignments:

  • chk2pulseactive_elim = 0

trigOFF

Trigger: geq(time, trigOFFtime)

Delay: 0

Assignments:

  • chk2pulseactive_elim_elim = 1

Constraints

Note that constraints are not enforced in simulations. It remains the responsibility of the user to verify that simulation results satisfy these constraints.


Species:

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Minimum criteria for DNA damage-induced phase advances in circadian rhythms.

  • Christian I Hong
  • Judit Zámborszky
  • Attila Csikász-Nagy
PLoS Comput. Biol. 2009; 5 (5):
Abstract
Robust oscillatory behaviors are common features of circadian and cell cycle rhythms. These cyclic processes, however, behave distinctively in terms of their periods and phases in response to external influences such as light, temperature, nutrients, etc. Nevertheless, several links have been found between these two oscillators. Cell division cycles gated by the circadian clock have been observed since the late 1950s. On the other hand, ionizing radiation (IR) treatments cause cells to undergo a DNA damage response, which leads to phase shifts (mostly advances) in circadian rhythms. Circadian gating of the cell cycle can be attributed to the cell cycle inhibitor kinase Wee1 (which is regulated by the heterodimeric circadian clock transcription factor, BMAL1/CLK), and possibly in conjunction with other cell cycle components that are known to be regulated by the circadian clock (i.e., c-Myc and cyclin D1). It has also been shown that DNA damage-induced activation of the cell cycle regulator, Chk2, leads to phosphorylation and destruction of a circadian clock component (i.e., PER1 in Mus or FRQ in Neurospora crassa). However, the molecular mechanism underlying how DNA damage causes predominantly phase advances in the circadian clock remains unknown. In order to address this question, we employ mathematical modeling to simulate different phase response curves (PRCs) from either dexamethasone (Dex) or IR treatment experiments. Dex is known to synchronize circadian rhythms in cell culture and may generate both phase advances and delays. We observe unique phase responses with minimum delays of the circadian clock upon DNA damage when two criteria are met: (1) existence of an autocatalytic positive feedback mechanism in addition to the time-delayed negative feedback loop in the clock system and (2) Chk2-dependent phosphorylation and degradation of PERs that are not bound to BMAL1/CLK.
The SBML for this model was obtained from the BioModels database (BioModels ID: BIOMD0000000216). Biomodels notes: The figure 2C of the reference publication is reproduced. To reproduce figure 2C, the following initial conditions were used (as per the authors suggestion). This is different from that of the model. M=1.35; CP=0.039; CP2=0.088; TF=0.06; IC=0.44 (TFtot=0.5 & IC=TFtot-TF). JWS Online curation: This model was curated by reproducing the figures as described in the BioModels Notes.