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amara1

amara1

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Reactions

reaction_1

r01

species_2 + species_1 > species_3

reaction_10

r10

species_11 > species_4 + species_12

reaction_11

r11

species_8 + species_18 > species_15

reaction_12

r12

species_12 + species_13 > species_14

reaction_13

r13

species_14 > species_12 + species_13

reaction_14

r14

species_14 + species_15 > species_16

reaction_15

r15

species_16 > species_14 + species_15

reaction_16

r16

species_16 > species_18 + species_17

reaction_17

r17

species_17 > species_13 + species_19

reaction_18

r18

species_13 + species_19 > species_17

reaction_19

r19

species_15 + species_17 > species_20

reaction_2

r02

{2.0}species_5 > species_4

reaction_20

r20

species_20 > species_15 + species_17

reaction_21

r21

species_20 > species_18 + species_21

reaction_22

r22

species_21 > species_13 + species_22

reaction_23

r23

species_12 > species_8 + species_23

reaction_24

r24

species_19 > {2.0}species_8 + species_23

reaction_25

r25

species_22 > {3.0}species_8 + species_23

reaction_3

r03

species_4 > {2.0}species_5

reaction_4

r04

species_6 + species_8 > species_7

reaction_5

r05

species_3 + species_4 > species_9

reaction_6

r06

species_9 > species_3 + species_4

reaction_7

r07

species_7 + species_9 > species_10

reaction_8

r08

species_10 > species_7 + species_9

reaction_9

r09

species_10 > species_6 + species_11

Parameters

Global parameters
reaction_1
reaction_10
reaction_11
reaction_12
reaction_13
reaction_14
reaction_15
reaction_16
reaction_17
reaction_18
reaction_19
reaction_2
reaction_20
reaction_21
reaction_22
reaction_23
reaction_24
reaction_25
reaction_3
reaction_4
reaction_5
reaction_6
reaction_7
reaction_8
reaction_9

Fixed species

Initial values

Functions and Rules

Assignment rules

parameter_1 = species_12 + species_19 + species_22 + species_11 + species_14 + species_17 + species_21 + species_20 + species_16

Function definitions

Events

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:

Reactions:

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log scales

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x-axis min/max

In vivo and in silico analysis of PCNA ubiquitylation in the activation of the Post Replication Repair pathway in S. cerevisiae.

  • Flavio Amara
  • Riccardo Colombo
  • Paolo Cazzaniga
  • Dario Pescini
  • Attila Csikász-Nagy
  • Marco Muzi Falconi
  • Daniela Besozzi
  • Paolo Plevani
BMC Syst Biol 2013; 7 : 24
Abstract
BACKGROUND: The genome of living organisms is constantly exposed to several damaging agents that induce different types of DNA lesions, leading to cellular malfunctioning and onset of many diseases. To maintain genome stability, cells developed various repair and tolerance systems to counteract the effects of DNA damage. Here we focus on Post Replication Repair (PRR), the pathway involved in the bypass of DNA lesions induced by sunlight exposure and UV radiation. PRR acts through two different mechanisms, activated by mono- and poly-ubiquitylation of the DNA sliding clamp, called Proliferating Cell Nuclear Antigen (PCNA).
RESULTS: We developed a novel protocol to measure the time-course ratios between mono-, di- and tri-ubiquitylated PCNA isoforms on a single western blot, which were used as the wet readout for PRR events in wild type and mutant S. cerevisiae cells exposed to acute UV radiation doses. Stochastic simulations of PCNA ubiquitylation dynamics, performed by exploiting a novel mechanistic model of PRR, well fitted the experimental data at low UV doses, but evidenced divergent behaviors at high UV doses, thus driving the design of further experiments to verify new hypothesis on the functioning of PRR. The model predicted the existence of a UV dose threshold for the proper functioning of the PRR model, and highlighted an overlapping effect of Nucleotide Excision Repair (the pathway effectively responsible to clean the genome from UV lesions) on the dynamics of PCNA ubiquitylation in different phases of the cell cycle. In addition, we showed that ubiquitin concentration can affect the rate of PCNA ubiquitylation in PRR, offering a possible explanation to the DNA damage sensitivity of yeast strains lacking deubiquitylating enzymes.
CONCLUSIONS: We exploited an in vivo and in silico combinational approach to analyze for the first time in a Systems Biology context the events of PCNA ubiquitylation occurring in PRR in budding yeast cells. Our findings highlighted an intricate functional crosstalk between PRR and other events controlling genome stability, and evidenced that PRR is more complicated and still far less characterized than previously thought.
The SBML for this model was obtained from the BioModels database (BioModels ID: BIOMD0000000475) Biomodels notes: The paper has plots that correspond to different UV irradiation dose (5, 10, 50, 75J/m^2, etc.). The condition encoded in this model correspond to a UV irradiation of 5J/m^2, that should reproduce Figure 2B of the paper. Here, Figure 2B of the paper is reproduced. An assignment rule for PCNA_poly (i.e. PCNA_sum - the sum of every species in which PCNA isoforms (included complex) are involved) has been added to model to obtain the figure. The model time is in seconds and So, to run the simulation for 300mins, it has to be run for 18000(300x60) seconds. The model was simulated using Copasi v4.10 (Build 55) and the plots were generated using Gnuplot. JWS Online curation: This model was curated by reproducing Figure 2B PCNAonU.