Scaffold/Matrix Attachment Regions (S/MARs): Relevance for Disease and Therapy

PARP-1 Expression in the Mouse is Controlled by an Autoregulatory Loop: PARP-1 Binding to an Upstream S/MAR Element and to a Novel Recognition Motif in its Promoter Suppresses Transcription

“…Among these, the poly (ADPribosyl)ation of histones resolves certain inter-and intra-nucleosomal DNA-histone interactions, thereby facilitating access to the damaged DNA by molecules that participate in its repair. 3 Unlike PARP-1 enzymatic activity, it is not clear to what extent DNA strand breaks activate PARP-1 gene transcription and, despite the earlier reports that motivated the present study, 4,5 details of the molecular mechanisms that regulate PARP-1 gene expression remain to be elucidated. So far, PARP-1 gene promoters have been identified and cloned for humans 6 , rats 7 and mice (GenBank-GeneID D14553S19) †.…”

“…Since base-unpairing is an established property of scaffold/matrix attachment regions (S/MARs), altered protein contacts are anticipated to contribute to a dynamic modulation of chromatin domains. Other studies have implicated PARP-1 in the regulation of gene expression 3,15 by direct binding to discontinuities in DNA structure such as three-or four-way junctions or bent DNA. 5 An important prerequisite for the formation of these structures is again the DNA baseunpairing potential, i.e.…”

“…3 How is this background level maintained? Earlier studies from this laboratory demonstrated that under physiological conditions a major part of PARP-1 co-localizes with lamin B at the nuclear periphery, where it remains in an activatable state.…”

“…16 Most important in the present context are observations that PARP-1, by binding to BUR-related structures in its promoter, down-regulates its own expression. 5,17 According to our model, 3 this process may involve the PARP-1-mediated translocation of its own gene into a silencing nuclear compartment (see below). In addition to its direct effects on chromatin architecture, PARP-1 can alter gene transcription by its ability to modify, by post-translational poly(ADP-ribosyl)ation, transcription factors such as SP1, 18 YY1, 3,12 NF-κB, 19 TFIIF, 20 Oct-1, 21 B-MYB, 22 AP-1, 23 cAMP-response element-binding protein, 24 and AP-2, 25 thus preventing their association with promoter target sites.…”

SAFB1's multiple functions in biological control—lots still to be done!

“…Indeed, SAFB1 binds to AT-rich S/MARs [Nayler et al, 1998a,b] which may provide the basis for higher order chromatin structure and are thought to partition chromatin into distinct topologically independent loops [Bode et al, 1996]. S/MARs have also been shown to be important in modulation of gene expression and in disease processes including cancer [Bode et al, 2000;Gluch et al, 2008]. Similar to S/MARs, base unpairing regions (BURs) are regions in DNA which are of critical importance to higher order chromatin regulation, presumably due their effects regional DNA unwinding and thus enhancement of dynamics accessibility of chromatin [Bode et al, 1992].…”