The cost of publication in Journal of Biomedical Science is borne by the National Science Council, Taiwan.
Research
Functional cooperation between FACT and MCM is coordinated with cell cycle and differential complex formation
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* Corresponding authors: Bertrand CM Tan btan@mail.cgu.edu.tw - Sheng-Chung Lee slee@ntu.edu.tw
- † Equal contributors
1 Department of Life Science, College of Medicine, Chang Gung Univeristy, Taoyuan, Taiwan
2 Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
3 Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
Journal of Biomedical Science 2010, 17:11 doi:10.1186/1423-0127-17-11
Published: 16 February 2010Abstract
Background
Functional cooperation between FACT and the MCM helicase complex constitutes an integral step during DNA replication initiation. However, mode of regulation that underlies the proper functional interaction of FACT and MCM is poorly understood.
Methods & Results
Here we present evidence indicating that such interaction is coordinated with cell cycle progression and differential complex formation. We first demonstrate the existence of two distinct FACT-MCM subassemblies, FACT-MCM2/4/6/7 and FACT-MCM2/3/4/5. Both complexes possess DNA unwinding activity and are subject to cell cycle-dependent enzymatic regulation. Interestingly, analysis of functional attributes further suggests that they act at distinct, and possibly sequential, steps during origin establishment and replication initiation. Moreover, we show that the phosphorylation profile of the FACT-associated MCM4 undergoes a cell cycle-dependent change, which is directly correlated with the catalytic activity of the FACT-MCM helicase complexes. Finally, at the quaternary structure level, physical interaction between FACT and MCM complexes is generally dependent on persistent cell cycle and further stabilized upon S phase entry. Cessation of mitotic cycle destabilizes the complex formation and likely leads to compromised coordination and activities.
Conclusions
Together, our results correlate FACT-MCM functionally and temporally with S phase and DNA replication. They further demonstrate that enzymatic activities intrinsically important for DNA replication are tightly controlled at various levels, thereby ensuring proper progression of, as well as exit from, the cell cycle and ultimately euploid gene balance.