title: Regulating the levels of key factors in cell cycle and DNA repair: new pathways revealed by lamins.
abstract: Spatial and temporal organization of the genome represents an additional step in the regulation of nuclear functions. The nuclear lamina, a polymeric meshwork formed by lamins (A/C and B type) and lamin-associated proteins, plays a key role in the maintenance of genome localization, structure and function. Specifically, mutations in the LMNA gene encoding lamins A/C or changes in its expression, either upregulation or silencing, are associated with defects in DNA replication, transcription and repair, as well as alterations in epigenetic modifications of chromatin. These data, together with the fact that defects in A-type lamins are associated with a whole variety of degenerative disorders, premature aging syndromes and cancer, support the notion that these proteins operate as caretakers of the genome. However, our understanding of their functions is limited due to the lack of well-defined mechanisms behind the genomic instability observed in lamin-related diseases. Here, we summarize our recent discovery of new pathways that are affected by the loss of A-type lamins. In particular, we found that A-type lamins control transcription and degradation of proteins with key roles in cell cycle regulation and DNA double-strand breaks (DSBs) repair by non-homologous end-joining (NHEJ) and homologous-recombination (HR). Importantly, the proteins regulated by A-type lamins--Rb family members, 53BP1, BRCA1 and RAD51--exert tumor suppressor functions, with their loss being associated with cancer susceptibility. Moreover, our studies revealed novel pathways that contribute to genomic instability and that can be activated in disease states independent of the status of A-type lamins.
authors: Department of Radiation Oncology, Radiation and Cancer Biology Division, Washington University School of Medicine, St. Louis, MO, USA.
authors: Abena B
authors: AB
authors: Redwood
authors: Ignacio
authors: I
authors: Gonzalez-Suarez
authors: Susana
authors: S
authors: Gonzalo
mesh_terms: D000818:Animals; D002453:Cell Cycle; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D042822:Genomic Instability; D006801:Humans; D034882:Lamins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008957:Models, Genetic; D014807:Vitamin D / Q000378:metabolism / Q000502:physiology
chemical_list: D034882:Lamins; D014807:Vitamin D