While diverse enzymatic activities are required for transcriptional initiation, a central question remains whether additional enzymatic activities involved in other cellular processes may also be critical for regulated gene activation. Recently, we reported that signal-dependent activation of gene transcription requires topoisomerase IIβ (Topo IIβ)-dependent, nucleosome-specific, transient double-stranded DNA break formation with subsequent activation of poly(ADP-ribose) polymerase-1 (PARP-1) enzymatic function, which causes local changes of chromatin architecture novel mechanistic link between gene transcription and components of the DNA damage/repair machinery, (Ju et al., Science 2006; 312: 1798-1802). Here, we discussed that possible molecular mechanism underling Topo IIβ/PARP-1/DNA-PK network in transcriptional initiation and many intriguing issues remain to be solved in the future.