Conceptually, the TLK model (Stewart 2001) is very similar to the RMR model (Tobias 1985).  However, the TLK postulates that radiation effectively creates two kinds of DSB, simple and complex DSBs, whereas the RMR postulates one kind of DSB.  Rejoining kinetics in the RMR is effectively monophasic.  In the TLK, DSB rejoining kinetics may be either monophasic or biphasic.

Although the TLK provides a more flexible framework for modeling DSB formation and repair processes than the RMR (or the LPL), the increased flexibility of this model has a price, i.e., additional parameters are introduced into the modeling process.  The RMR has five main adjustable parameters (see Tutorial 2.2).  As many as eight key parameters may be considered adjustable within the TLK.  The eight key parameters are:

1. Yield of simple and complex DSB Gy^-1 cell^-1. Specify total DSB yield using the DSB={value} keyword.  The FCB={value} or NED={value} parameters are then used to partition the DSB yield into simple and complex DSBs.
2. Probability a DSB is repaired incorrectly.  Specify using the A0={pointer to array of two values} or B0={pointer to array of two values} keywords.  A0 and B0 are related by A0=(1-B0).
3. Probability a misrepaired DSB is lethal.  Specify using the PHI={value}.  NOTE: (1-PHI) is the probability a misrepaired DSB is not lethal.  The PHI value is used for misrepaired simple and complex DSBs.
4. 1^st order DSB rejoining rate. Specify using the LAM={array of two values} keyword or RHT={array of two values} keyword. The LAM and RHT parameters are related by LAM = LN(2)/RHT.
5. Rate of pairwise damage interaction (2^nd order DSB rejoining rate). Specify using the ETA={value} keyword.

1. Paste the contents of TLK sample file #1 into a new ASCII input file called tlk1.inp.
2. Set the fraction of the complex DSBs (FCB parameter) to zero.  Run the simulation.
3. Repeat step 2 for values of FCB from 0 (all DSBs are simple DSBs) to 1 (all DSBs are complex DSBs).
4. Create a plot showing the surviving fraction (y-axis, linear scale) vs. FCB (x-axis, linear scale).
5. Create a plot showing the LQ radiosensitivity parameter a (y-axis, linear scale) vs. FCB (x-axis, linear scale).
6. Create a plot showing the LQ radiosensitivity parameter a/b (y-axis, linear scale) vs. FCB (x-axis, linear scale).

• Does the surviving fraction increase, decrease or stay the same as FCB increases?
• Does a and a/b increase, decrease or stay the same as FCB increases?
• Explain the observed trends in the surviving fraction, a and a/b in terms of first- and second-order repair processes.  Hint: As the value of FCB increases, does the first-order rejoining rate increase or decrease?

1. Paste the contents of TLK sample file #1 into a new ASCII input file called tlk2.inp.
2. Set the half-time for fast DSB rejoining to 0.1 h (RHT parameter).  Run the simulation.
3. Repeat step 2 for repair half-times from 0.1 h to 6 h.
4. Create a plot of the surviving fraction (y-axis, linear scale) vs. the half-time for fast DSB rejoining (x-axis, linear scale).

• Does the surviving fraction increase, decrease or stay the same as the half-time for fast DSB rejoining increases?
• Are fast rejoining DSBs more or less likely to interact in pairwise fashion as the half-time increases?
• Do these studies suggest that most of the cell killing is due to the fast or slow rejoining DSBs?  Can you think of any reasons why this model prediction might not be true?  Hint: Some DSBs might be rejoined by non-homologous endjoining (NHEJ) while others may be repaired by homologous recombination (HR).  The kinetics and accuracy of these two repair mechanisms may be quite different.