Structural and evolutionary implications of the packaging of DNA for differentiation and proliferation in the lymphocyte

Summary

During the differentiation of the clonally distributed lymphocytes of mouse and man into mature resting B and T cells, their DNA becomes tightly packed into dense heterochromatin masses and exhibits very little transcriptional activity; it also becomes extensively nicked, containing some 3000–4000 single-strand breaks per diploid genome. The nuclear matrix is sparse and poorly organized and there are but trace amounts of the matrix-linked enzyme DNA topoisomerase II; the nucleus of these small cells is surrounded by a thin rim of cytoplasm. The resting cell can thus be considered (by analogy to a sperm cell) as a vector for transporting tightly packed and relatively inert genetic information to all parts of the body. When the lymphocyte is stimulated to enter a proliferative cycle by binding of appropriately presented antigen or mitogen to relevant membrane receptors, the cell enlarges, due to increased synthesis of protein; the dense heterochromatin is pulled out into very small clumps, as a result of an enormous growth in size as well as complexity of the nuclear matrix, and a great increase in transcriptional activity occurs. We have identified four nuclear matrix antigens that are very widely conserved in the evolution of eucaryotes and that occupy distinctive domains in interphase nuclei. Of particular interest is antigen P1, detected in organisms ranging from algae to mammals. By virtue of its location at the interface between nuclear envelope and chromatin, we propose that it plays a major and evolutionarily conserved role in chromatin organization and orientation in all eucaryotic cell types. Prior to these events, the DNA strand breaks are rejoined by a mechanism dependent on poly(ADP ribose) synthetase; rejoining of the breaks is required in order for the cells to enter the S phase of the cell cycle. Under certain experimental conditions, the induction of DNA topoisomerase II is clearly seen to precede DNA replication; topoisomerase II may be involved in some of the nuclear changes of blastogenesis. The evidence suggests that induction of single-strand breaks in DNA may be a general feature in the evolution of differentiated somatic cells. The selective advantage of the endogenously produced DNA strand breaks may be to provide an additional mechanism that prevents the differentiated cell from replicating its genome in the absence of an appropriate proliferative signal.