This article is a perspective on the separation of the complementary strand
s of DNA during replication. Given the challenges of DNA strand separation
and its vital importance, it is not surprising that cells have developed ma
ny strategies for promoting unlinking. We summarize seven different factors
that contribute to strand separation and chromosome segregation. These are
: (1) supercoiling promotes unlinking by condensation of DNA; (2) unlinking
takes place throughout a replicating domain by the complementary action of
topoisomerases on precatenanes and supercoils; (3) topological domains iso
late the events near the replication fork and permit the supercoiling-depen
dent condensation of partially replicated DNA; (4) type-II topoisomerases u
se ATP to actively unlink DNA past the equilibrium position; (5) the effect
ive DNA concentration in vivo is less than the global DNA concentration; (6
) mechanical forces help unlink chromosomes; and (7) site-specific recombin
ation promotes unlinking at the termination of replication by resolving cir
cular dimeric chromosomes.