Poly(ADP-Ribose) Polymerase Binds with Transcription Enhancer Factor 1 to MCAT1 Elements To Regulate Muscle-Specific Transcription

Abstract

Multicellular organisms express many genes in a cell-typespecific fashion. The mechanisms governing cell-specific gene expression are becoming increasingly understood at two levels. First, there are numerous examples in which the binding of nuclear transcription factors to cis elements within gene regulatory regions has been shown to govern cell-specific activation of gene transcription. A second level of regulation has been proposed to be mediated by the remodeling of chromatin organization both globally and at individual gene loci. Chromatin remodeling itself encompasses many types of changes, including nucleosome phasing, alterations of chromosomal protein content (histone and nonhistone), and posttranslational modification of chromosomal proteins by acetylation, phosphorylation, poly(ADP-ribosyl)ation, methylation, and ubiquitination (6). Although it is widely acknowledged that both levels must govern the cell-specific expression of individual genes, there has been little information as to mechanisms that might integrate these two levels of regulation. Recently, however, histone acetyltransferases have been shown to bind to specific trans-acting factors (recently reviewed in references 22, 29, and 55). Such protein-protein binding suggests a mechanism by which chromatin histones can be modified locally (as opposed to globally) through binding of histone acetyltransferases to transcription factors that are in turn bound to DNA cis elements within the regulatory regions of specific genes. We report here a new mechanism by which these two levels of gene regulation can be integrated; through direct binding of the chromatin-modifying protein, poly(ADP-ribose) polymerase (PARP), to DNA sequences within MCAT1 regulatory elements.

Factors controlling cardiac myosin-isoform shift during hypertrophy and heart failure

“…PARP1, a prototype member of the large PARP family, has been shown to interact with TEF1 to form a complex on M-CAT binding sites of the cardiac troponinT and MHC genes, leading to their muscle-specific gene regulation [136,137]. We as well as others have previously reported that PARP1 is activated during both physiologic and pathologic hypertrophy, and that its levels are further elevated in failing hearts [107,135,138].…”

“…In regard to what is known about the intracellular stimuli of PARP1, at least two signaling pathways, an increased intracellular Ca 2+ level and the activation of ERK1/2, have been found to activate PARP1 during hypertrophy [140,141]. By analysis of PARP-inhibitors, it was found that PARP activates the TEF1-mediated gene transcription from the M-CAT sites [136]. In contrast, in a transient assay, over expression of PARP1 was found to repress the transcription of genes containing the M-CAT sites, again suggesting that PARP1 has a dual role in gene expression, activation followed by repression, depending upon the degree of PARP activation [107].…”

Overexpression of dominant negative PARP interferes with tumor formation of HeLa cells in nude mice: Evidence for increased tumor cell apoptosis in vivo

“…repair proteins and the biological e ects observed are solely due to the absence of poly(ADP-ribosyl)ation. By contrast, knocking out PARP either by homologous recombination or by expressing PARP antisense RNA interferes with any function of PARP protein, including poly(ADP-ribosyl)ation, binding to DNA strand breaks and, as shown recently, in¯uences on transcription (Oei et al, 1998;Butler and Ordahl, 1999). Thus it is conceivable that, if PARP has several functions, a complete loss of all of these functions due to gene targeting or antisense technology can result in a di erent phenotype than loss of only one function such as catalytic activity.…”

Poly(ADP-ribose) polymerase upregulates E2F-1 promoter activity and DNA pol α expression during early S phase

“…The role of PARP in the regulation of transcription of the E2F-1 and pol a genes may be indirect, given that PARP has also been shown to enhance activator-dependent transcription by interacting with RNA polymerase II-associated factors (Meisterernst et al, 1997). PARP also binds transcription enhancer factor 1 (TEF1) to enhance muscle-speci®c gene transcription (Butler and Ordahl, 1999) as well as the transcription factor AP-2 to coactivate AP-2-mediated transcription (Kannan et al, 1999). The basal transcription factor TFIIF and TEF-1 are both highly speci®c substrates for poly(ADPribosyl)ation (Butler and Ordahl, 1999;Rawling and Alvarez-Gonzalez, 1997).…”

“…PARP also binds transcription enhancer factor 1 (TEF1) to enhance muscle-speci®c gene transcription (Butler and Ordahl, 1999) as well as the transcription factor AP-2 to coactivate AP-2-mediated transcription (Kannan et al, 1999). The basal transcription factor TFIIF and TEF-1 are both highly speci®c substrates for poly(ADPribosyl)ation (Butler and Ordahl, 1999;Rawling and Alvarez-Gonzalez, 1997). Whether PARP modulates E2F-1-mediated transcription by binding to E2F-1 remains to be clari®ed.…”