Abstract:
Genotoxic stress generates single- and double-strand DNA breaks either through direct damage by
reactive oxygen species or as intermediates of DNA repair. Failure to detect and repair DNA strand
breaks leads to deleterious consequences such as chromosomal aberrations, genomic instability
and cell death. DNA strand breaks disrupt the superhelical state of cellular DNA, which further
disturbs the chromatin architecture and gene activity regulation. Proteins from the poly(ADP ribose) polymerase (PARP) family, such as PARP1 and PARP2, use NAD+ as a substrate to catalyse
the synthesis of polymeric chains consisting of ADP-ribose units covalently attached to an acceptor
molecule. PARP1 and PARP2 are regarded as DNA damage sensors that, upon activation by strand
breaks, poly(ADP-ribosyl)ate themselves and nuclear acceptor proteins. Noteworthy, the regularly
branched structure of poly(ADP-ribose) polymer suggests that the mechanism of its synthesis
may involve circular movement of PARP1 around the DNA helix, with a branching point in PAR
corresponding to one complete 360° turn. We propose that PARP1 stays bound to a DNA strand
break end, but rotates around the helix displaced by the growing poly(ADP-ribose) chain, and that
this rotation could introduce positive supercoils into damaged chromosomal DNA. This topology
modulation would enable nucleosome displacement and chromatin decondensation around the
lesion site, facilitating the access of DNA repair proteins or transcription factors. PARP1-mediated
DNA supercoiling can be transmitted over long distances, resulting in changes in the high-order
chromatin structures. The available structures of PARP1 are consistent with the strand break induced PAR synthesis as a driving force for PARP1 rotation around the DNA axis.