The Drosophila heterochromatic gene encoding poly(ADP-ribose) polymerase (PARP) is required to modulate chromatin structure during development

Abstract

Poly(ADP-ribose) polymerase (PARP) is a major NAD-dependent modifying enzyme that mediates important steps in DNA repair, transcription, and apoptosis, but its role during development is poorly understood. We found that a single Drosophila Parp gene spans more than 150 kb of transposon-rich centromeric heterochromatin and produces several differentially spliced transcripts, including a novel isoform, PARP-e, predicted to encode a protein lacking enzymatic activity. An insertion mutation near the upstream promoter for Parp-e disrupts all Parp expression. Heterochromatic but not euchromatic sequences become hypersensitive to micrococcal nuclease, nucleoli fail to form, and transcript levels of the copia retrotransposon are elevated more than 50-fold; the variegated expression of certain transgenes is dominantly enhanced. Larval lethality can be rescued and PARP activity restored by expressing a cDNA encoding PARP-e. We propose that PARP-e autoregulates Parp transcription by influencing the chromatin structure of its heterochromatic environment. Our results indicate that Parp plays a fundamental role organizing the structure of Drosophila chromatin.

PARP-10, a novel Myc-interacting protein with poly(ADP-ribose) polymerase activity, inhibits transformation

“…While in mammals the PARP family is rather large, only two PARP enzymes, a PARP-1 and a tankyrase-1 ortholog, have been reported in Drosophila (Tulin et al, 2002). In agreement, PARP-10 orthologs could be identified neither in Drosophila nor in Caenorhabditis elegans (data not shown).…”

“…In agreement, PARP-10 orthologs could be identified neither in Drosophila nor in Caenorhabditis elegans (data not shown). In Drosophila, PARP-1 is required for chromatin organization and is associated with areas of high transcriptional activity and decondensed chromatin (chromosomal puffs) (Tulin et al, 2002;Tulin and Spradling, 2003). Gene activation in response to stress and steroid hormones results in an increase in poly (ADP-ribosyl)ated proteins at the responsive loci, which is required to obtain normal-sized puffs and efficient gene expression.…”

Differential expression in lupus-associated IL-10 promoter single-nucleotide polymorphisms is mediated by poly(ADP-ribose) polymerase-1

“…PARP-1 has been linked to multiple events for transcriptional regulation in development. [61][62][63][64] A large body of evidence shows that PARP-1 is activated during the inflammatory response, contributing to tissue damage. Accordingly, pharmacological inhibition of PARP-1 has shown therapeutic efficacy in animal models of inflammation such as ischemia-reperfusion, 60 chronic colitis, 65 asthma, 66 autoimmune encephalomyelitis, 67 diabetes mellitus, 68 and PARP À/À mice are protected from endotoxic shock.…”

Uncoupling of the transactivation and transrepression functions of PARP1 protein

“…Moreover, it has been shown that PARP1 regulates the transcription of these genes by inducing chromatin loosening at targeted genetic loci (6,7). Finally, PARP1 establishes silent chromatin domains and represses retrotransposable elements (8).…”

“…Closing these gaps in our current knowledge is complicated because the presence of 18 paralogous PARP proteins (9) in mammals most likely results in corresponding functional redundancies. The Drosophila genome (8,10,11) encodes only a single nuclear PARP (PARP1), making this animal an invaluable model system for the study of PARP functions.…”