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2009.99: A stochastic-hybrid Model of DNA replication in mammalian cells

2009.99: Alexander G. Shaw, Robert J. Platt, Jennifer K. Withers, Nils Blüthgen, Kieran Smallbone and Dean A. Jackson (2009) A stochastic-hybrid Model of DNA replication in mammalian cells.

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Abstract

Background This study presents a mathematical model which explores the mechanisms of human S phase that link different patterns of synthesis with the temporal S phase programme, which is seen in vivo. A chromosome and genome-wide scale is used in the modelling, which focuses on the behaviour of replication factories relative to the chromatin template. DNA foci that contain ~1Mbp of DNA are the functional units of synthesis and provide targets for the synthetic process, with each focus containing clusters of replicons that are replicated together within a single dedicated replication factory.

Results The model indicates that random replication factory placement and/or dynamics cannot lead to the observed S phase progression pattern. However, co-ordination of factory activation according to Giemsa staining bands, with bias towards R-bands over G-bands, results in a transition from R- to G-band replication after 3-5hours. Our model predicts that factories move between chromosomes to avoid non-uniform entry into late S-phase. The distribution of replicons has a strong influence on simulations, with grouping of similar sized replicons making replication more efficient.

Conclusions Mathematical modelling of the mammalian cell S phase provides insight into the organisation of the human genome. For example, the co-ordinated targeting of replication factories to R- and G-bands based on their structural properties and distribution in nuclei can explain the temporal progression of synthesis that is observed in experimental studies. However, further understanding of the S phase programme is likely to require additional spatial information and incorporate a three dimensional approach.

Item Type:MIMS Preprint
Subjects:MSC 2000 > 92 Biology and other natural sciences
MIMS number:2009.99
Deposited By:Dr Kieran Smallbone
Deposited On:14 December 2009

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