title: Role of lamin b1 in chromatin instability.
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.
authors.affiliation: Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Veronika
authors.initials: V
authors.lastname: Butin-Israeli
authors.affiliation: Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Adam
authors.affiliation: Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Jain
authors.affiliation: Epigenetics Program, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Gabriel L
authors.initials: GL
authors.lastname: Otte
authors.affiliation: Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Neems
authors.affiliation: Department of Obstetrics and Gynecology, Ulm University, Ulm, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Wiesmüller
authors.affiliation: Epigenetics Program, Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Shelly L
authors.initials: SL
authors.lastname: Berger
authors.affiliation: Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA r-goldman@northwestern.edu.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Goldman
mesh_terms: D017209:Apoptosis; D019313:BRCA1 Protein / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry*; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D034921:Lamin Type B / Q000378:metabolism*; D034622:RNA Interference; D051135:Rad51 Recombinase / Q000378:metabolism; D016196:S Phase
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D002843:Chromatin; D034921:Lamin Type B; C495153:RAD51 protein, human; D051135:Rad51 Recombinase