Long Range Force between Pre-Replication Complexes (Pre-RC) in DNA Controls Replication and Cell Cycle Progression

Abstract

A nonstationary interaction, that controls DNA replication and the cell cycle, is derived from a manybody physics model in a chemically open T cell. The model predicts a long range force F'(ξ)=-(κ/2) ξ(1-ξ)(2-ξ) between the pre-replication complexes (pre-RCs) bound by DNA, ξ=ϕ/N being the relative displacement of preRCs, ϕ the number of pre-RCs, N the threshold for initiation, and κ the compressibility modulus in thelattice of pre-RCs which behaves like an elastically braced string. Initiation of DNA replication is induced by a switch of sign of F'(ξ), from attraction (-)and assembly in the G(1) phase (0 < ϕ < N), to repulsion (+) and partialdisassembly in the S phase (N < ϕ < 2N), with release of licensing factors from the pre-RCs, thus explaining prevention of re-replication. Replication is terminated by a switch of sign of F at ϕ = 2N, when all primed replicons are duplicated once, and F(0)=0 corresponds to a resting cell in absence of driving force at ϕ = 0. The switch of sign of force at ϕ = N also explains the dynamic instability in growing microtubules (MTs), as well as switch in the interleukin-2 (IL2) interaction with its receptor in late G(1), at the restriction point. Shape, slope and scale of the response curves derived agree well with experimental data from dividing T cells and polymerizing MTs, the variable length of which is due to anonlinear dependence of the growth amplitude on the initial concentrations of tubulin dimers and guanosine-tri-phosphate (GTP).

Keywords: DNA replication; Rb protein; cell cycle control; cyclin dependent kinases; origin recognition complex.