TY - JOUR
T1 - Regulating the levels of key factors in cell cycle and DNA repair
T2 - New pathways revealed by lamins
AU - Redwood, Abena B.
AU - Gonzalez-Suarez, Ignacio
AU - Gonzalo, Susana
PY - 2011/11/1
Y1 - 2011/11/1
N2 - 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 laminrelated 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 nonhomologous endjoining (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.
AB - 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 laminrelated 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 nonhomologous endjoining (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.
KW - A-type lamins
KW - Cell cycle
KW - DNA repair
KW - Proteases
KW - Vitamin D
UR - http://www.scopus.com/inward/record.url?scp=80655140622&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80655140622&partnerID=8YFLogxK
U2 - 10.4161/cc.10.21.18201
DO - 10.4161/cc.10.21.18201
M3 - Review article
C2 - 22045204
AN - SCOPUS:80655140622
SN - 1538-4101
VL - 10
SP - 3652
EP - 3657
JO - Cell Cycle
JF - Cell Cycle
IS - 21
ER -