Relationships between replication timing and GC content of cancer-related genes on human chromosomes 11q and 21q.

The human genome is composed of large-scale compartmentalized structures, including long G+C% (GC%) mosaic structures and replication-timing zones, which are related to chromosome band zones. Previously, we measured replication timing along the entire lengths of human chromosomes 11q and 21q at the sequence level, and it was suggested that the transition regions of replication timing from early to late S-phase coincided with "unstable" regions of the genome associated with increased DNA damage. In the present study, we measured replication timing of 15 known oncogenes and tumor suppressor genes on human chromosomes 11q and 21q using two human cell lines (THP-1 and Jurkat). We found unusual relationships between replication timing and the GC content of the genomic regions in which these cancer-related genes were located. Many of these genes showed similar replication timing between the two cell lines, and the majority replicated intermediately between early and late in both cell lines. On the other hand, more than half of these genes were located at very GC-rich (50-55 GC%) regions. In addition, we analyzed the exact relationships between early/late-switch regions of replication timing where cancer-related genes were located, and GC% transitions in and around five R/G-chromosomal band boundaries (each ca. 4 Mb) by using newly designed PCR primer sets. We found that the majority of cancer-related genes including oncogenes were located in GC-rich isochores close to GC% transitions within early/late-switch regions of replication timing, many of which replicated intermediately between the early and late S-phase. Unusual relationships between replication timing and GC content of the genomic regions in which cancer-related genes were located may be related to the molecular mechanisms of genomic instability associated with increased DNA damage.