Epigenetic control in DNA replication
doi:10.1038/nindia.2012.113 Published online 30 July 2012
New research claims to have stumbled upon a novel epigenetic control mechanism in DNA replication. An epigenetic mechanism is one that brings about changes in gene expression or cellular phenotype through mechanisms other than a change in the underlying DNA sequence.
Genetic information is transmitted from mother cells to daughter cells during successive cell division cycles. This happens through duplication of genomic DNA in the S-phase and its segregation in the M-phase. In order to duplicate large genomes of eukaryotic cells within S-phase, DNA replication happens from multiple sites of chromosomes called origins.
"Entry into S-phase is where the dices are thrown, where judicious choice of the origin determines the fate of the cell. This is also where a deregulated origin paves the way for genomic instability leading to tumorigenesis", says lead researcher Vijay Kumar of the virology group at New Delhi-based International Centre for Genetic Engineering and Biotechnology (ICGEB).
Cell cycle control of epigenetic and chromatin modifications at origins are suggested to be the key determinants. However, the regulation of replication initiation by specific chromatin signatures was enigmatic.
The researchers have proposed a new molecular model for the initiation of DNA replication. Their observation is based on an early replicating origin called 'Lamin B2'. The lamin B2 origin sequence carries an 'Enhancer box' (E-box) element for binding to a well-known transcription factor c-Myc. (E-box is a DNA sequence which usually lies upstream of a gene in a promoter region. It is a transcription factor binding site where a specific sequence of DNA is recognized by proteins that can bind to it to help initiate its transcription).
E-box normally remains in a methylated state which prevents Myc occupancy. Re-entry of cells to cell cycle sets out an exclusive active demethylation process that drives temporally tuned c-Myc occupancy on E-box. This is followed by other downstream relay events that promote the loading of Micro-chromosome maintenance (MCM) helicases and nucleosome remodelling of the origin.
The researchers say their work paves the way for establishing a more causal link of genome-wide effector molecules in transducing 'locus-specific replication initiation'.
- Swarnalatha, M. et al. The epigenetic control of E-box and Myc-dependent chromatin modifications regulate the licensing of lamin B2 origin during cell cycle. Nucl. Acids Res. doi: 10.1093/nar/gks617 (2012)