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© The Rockefeller University Press, 0021-9525/1997//1201 $5.00
The Journal of Cell Biology, Volume 136, Number 6, , 1997 1201-1212

Article

Disruption of Nuclear Lamin Organization Alters the Distribution of Replication Factors and Inhibits DNA Synthesis



Timothy P. Spann*, Robert D. Moir*, Anne E. Goldman*, Reimer Stick{ddagger}, and Robert D. Goldman*

* Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, Illinois 60611; and {ddagger} Institut fuer Biochemie und Molekulare Zellbiologie der Universität Goettingen, D-37073 Goettingen, Germany

The nuclear lamina is a fibrous structure that lies at the interface between the nuclear envelope and the nucleoplasm. The major proteins comprising the lamina, the nuclear lamins, are also found in foci in the nucleoplasm, distinct from the peripheral lamina. The nuclear lamins have been associated with a number of processes in the nucleus, including DNA replication. To further characterize the specific role of lamins in DNA replication, we have used a truncated human lamin as a dominant negative mutant to perturb lamin organization. This protein disrupts the lamin organization of nuclei when microinjected into mammalian cells and also disrupts the lamin organization of in vitro assembled nuclei when added to Xenopus laevis interphase egg extracts. In both cases, the lamina appears to be completely absent, and instead the endogenous lamins and the mutant lamin protein are found in nucleoplasmic aggregates. Coincident with the disruption of lamin organization, there is a dramatic reduction in DNA replication. As a consequence of this disruption, the distributions of PCNA and the large subunit of the RFC complex, proteins required for the elongation phase of DNA replication, are altered such that they are found within the intranucleoplasmic lamin aggregates. In contrast, the distribution of XMCM3, XORC2, and DNA polymerase {alpha}, proteins required for the initiation stage of DNA replication, remains unaltered. The data presented demonstrate that the nuclear lamins may be required for the elongation phase of DNA replication.

Abbreviations used in this paper: IF, intermediate filament; LA, lamin A; LB3, lamin B3; DIOC6, dihexyloxacarbocyanine.

This work is supported by grant CA31760 from the National Cancer Institute.

T.P. Spann and R.D. Moir contributed equally to this work.


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