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Published online April 21, 2008
doi:10.1083/jcb.200708155
The Journal of Cell Biology, Vol. 181, No. 2, 269-280
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Shumaker et al.
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Article

 The highly conserved nuclear lamin Ig-fold binds to PCNA: its role in DNA replication

Dale K. Shumaker1, Liliana Solimando1, Kaushik Sengupta1, Takeshi Shimi1, Stephen A. Adam1, Antje Grunwald2, Sergei V. Strelkov3, Ueli Aebi4, M. Cristina Cardoso2, and Robert D. Goldman1

1 Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
2 Max Delbrück Center for Molecular Medicine, D-13125 Berlin, Germany
3 Department of Pharmaceutical Sciences, Catholic University of Leuven, B-3000 Leuven, Belgium
4 Maurice E. Muller Institut, Biozentrum der Universitat, Basel CH-4056, Switzerland

Correspondence to R.D. Goldman: r-goldman{at}northwestern.edu

This study provides insights into the role of nuclear lamins in DNA replication. Our data demonstrate that the Ig-fold motif located in the lamin C terminus binds directly to proliferating cell nuclear antigen (PCNA), the processivity factor necessary for the chain elongation phase of DNA replication. We find that the introduction of a mutation in the Ig-fold, which alters its structure and causes human muscular dystrophy, inhibits PCNA binding. Studies of nuclear assembly and DNA replication show that lamins, PCNA, and chromatin are closely associated in situ. Exposure of replicating nuclei to an excess of the lamin domain containing the Ig-fold inhibits DNA replication in a concentration-dependent fashion. This inhibitory effect is significantly diminished in nuclei exposed to the same domain bearing the Ig-fold mutation. Using the crystal structures of the lamin Ig-fold and PCNA, molecular docking simulations suggest probable interaction sites. These findings also provide insights into the mechanisms underlying the numerous disease-causing mutations located within the lamin Ig-fold.

D.K. Shumaker and L. Solimando contributed equally to this paper.

A. Grunwald's present address is Albert Einstein College of Medicine, New York, NY 10461.

Abbreviations used in this paper: 11-dUTP, biotin-11-2'-deoxyuridine-5'-triphosphate; EDMD, Emery-Dreifuss muscular dystrophy; IF, intermediate filament; LA, lamin A; LB1, lamin B1; LB3, lamin B3; LC, lamin C; NLS, nuclear localization sequence; PCNA, proliferating cell nuclear antigen; PIP, PCNA-interacting protein; RFC, replication factor C; uS, ultracentrifuged supernatant.


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