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Abstract
Nuclear lamins play important roles in the organization and structure of the nucleus; however, the specific mechanisms linking lamin structure to nuclear functions are poorly defined. We demonstrate that reducing nuclear lamin B1 expression by short hairpin RNA-mediated silencing in cancer cell lines to approximately 50% of normal levels causes a delay in the cell cycle and accumulation of cells in early S phase. The S phase delay appears to be due to the stalling and collapse of replication forks. The double-strand DNA breaks resulting from replication fork collapse were inefficiently repaired, causing persistent DNA damage signaling and the assembly of extensive repair foci on chromatin. The expression of multiple factors involved in DNA replication and repair by both nonhomologous end joining and homologous repair is misregulated when lamin B1 levels are reduced. We further demonstrate that lamin B1 interacts directly with the promoters of some genes associated with DNA damage response and repair, including BRCA1 and RAD51. Taken together, the results suggest that the maintenance of lamin B1 levels is required for DNA replication and repair through regulation of the expression of key factors involved in these essential nuclear functions.
Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01145-14.
ACKNOWLEDGMENTS
R.D.G. was supported by NCI grant R01CA031760 and the Progeria Research Foundation. V.B.-I. was supported by a fellowship from the Gruss-Lipper Foundation. S.L.B. was supported by NIA P01 grant P01AG031862. G.L.O. was supported by a Computational Biology T32 NRSA Research Training Grant and PGFI Excellence in Genome Science.