Chromatin and nuclear matrix in development and in carcinogenesis - a theory

Sufficient evidence indicates that the nuclear matrix which organizes chromatin into loops or domains harbors origins of replication, homeodomain protein binding sites, and transcriptional enhancer sequences. Thus nuclear matrix might sculpture the crossroads of the differential gene expression and differential activation of origins of replication occurring during development. Nuclear matrix is also the site of transcription, replication, repair and recombination. These properties of the nuclear matrix are explored in the context of their implications in carcinogenesis. Many tumors result from abnormal translocations of DNA segments at other genomic sites via a recombination process involving some unusual DNA sequences at the breakpoints, such as Alu repetitive sequences or Z-DNA. Translocations are predicted to occur more frequently on the nuclear matrix and to involve DNA sequences at the bases of chromatin loops. Other tumors may result from the overexpression of distinct genes whose transcription regulation occurs at their nuclear matrix attachment sites. Tumorigenesis connected with mutations at coding DNA sequences is also related to the nuclear matrix, since nuclear matrix governs repair activities in the nucleus and might also harbor the most vulnerable DNA sites to damage and the most refractory to repair. These novel, and the previously known, features of the nuclear matrix reveal a new approach in understanding carcinogenesis.