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Poly-ADP ribosylation in DNA damage response and cancer therapy.

ABSTRACT: Poly(ADP-ribosyl)ation (aka PARylation) is a unique protein post-translational modification (PTM) first described over 50 years ago. PARylation regulates a number of biological processes including chromatin remodeling, the DNA damage response (DDR), transcription, apoptosis, and mitosis. The subsequent discovery of poly(ADP-ribose) polymerase-1 (PARP-1) catalyzing DNA-dependent PARylation spearheaded the field of DDR. The expanding knowledge about the poly ADP-ribose (PAR) recognition domains prompted the discovery of novel DDR factors and revealed crosstalk with other protein PTMs including phosphorylation, ubiquitination, methylation and acetylation. In this review, we highlight the current knowledge on PAR-regulated DDR, PAR recognition domain, and PARP inhibition in cancer therapy.

SUBMITTER: Hou WH

PROVIDER: S-EPMC6690395 | biostudies-literature | 2019 Apr - Jun

REPOSITORIES: biostudies-literature

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Poly-ADP ribosylation in DNA damage response and cancer therapy.

Hou Wei-Hsien WH Chen Shih-Hsun SH Yu Xiaochun X

Mutation research. Reviews in mutation research 20170920

Poly(ADP-ribosyl)ation (aka PARylation) is a unique protein post-translational modification (PTM) first described over 50 years ago. PARylation regulates a number of biological processes including chromatin remodeling, the DNA damage response (DDR), transcription, apoptosis, and mitosis. The subsequent discovery of poly(ADP-ribose) polymerase-1 (PARP-1) catalyzing DNA-dependent PARylation spearheaded the field of DDR. The expanding knowledge about the poly ADP-ribose (PAR) recognition domains pr ...[more]

PMID: 31395352

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PARP2 mediates branched poly ADP-ribosylation in response to DNA damage.

Project description:Poly(ADP-ribosyl)ation (PARylation) is a posttranslational modification involved in multiple biological processes, including DNA damage repair. This modification is catalyzed by poly(ADP-ribose) polymerase (PARP) family of enzymes. PARylation is composed of both linear and branched polymers of poly(ADP-ribose) (PAR). However, the biochemical mechanism of polymerization and biological functions of branched PAR chains are elusive. Here we show that PARP2 is preferentially activated by PAR and subsequently catalyzes branched PAR chain synthesis. Notably, the direct binding to PAR by the N-terminus of PARP2 promotes the enzymatic activity of PARP2 toward the branched PAR chain synthesis. Moreover, the PBZ domain of APLF recognizes the branched PAR chain and regulates chromatin remodeling to DNA damage response. This unique feature of PAR-dependent PARP2 activation and subsequent PARylation mediates the participation of PARP2 in DNA damage repair. Thus, our results reveal an important molecular mechanism of branched PAR synthesis and a key biological function of branched PARylation.

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The FHA and BRCT domains recognize ADP-ribosylation during DNA damage response.

Project description:Poly-ADP-ribosylation is a unique post-translational modification participating in many biological processes, such as DNA damage response. Here, we demonstrate that a set of Forkhead-associated (FHA) and BRCA1 C-terminal (BRCT) domains recognizes poly(ADP-ribose) (PAR) both in vitro and in vivo. Among these FHA and BRCT domains, the FHA domains of APTX and PNKP interact with iso-ADP-ribose, the linkage of PAR, whereas the BRCT domains of Ligase4, XRCC1, and NBS1 recognize ADP-ribose, the basic unit of PAR. The interactions between PAR and the FHA or BRCT domains mediate the relocation of these domain-containing proteins to DNA damage sites and facilitate the DNA damage response. Moreover, the interaction between PAR and the NBS1 BRCT domain is important for the early activation of ATM during DNA damage response and ATM-dependent cell cycle checkpoint activation. Taken together, our results demonstrate two novel PAR-binding modules that play important roles in DNA damage response.

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Acetylation blocks DNA damage-induced chromatin ADP-ribosylation.

Project description:Recent studies report serine ADP-ribosylation on nucleosomes during the DNA damage response. We unveil histone H3 serine 10 as the primary acceptor residue for chromatin ADP-ribosylation and find that specific histone acetylation marks block this activity. Our results provide a molecular explanation for the well-documented phenomenon of rapid deacetylation at DNA damage sites and support the combinatorial application of PARP and HDAC inhibitors for the treatment of PARP-dependent cancers.

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Function of BRCA1 in the DNA damage response is mediated by ADP-ribosylation.

Project description:Carriers of BRCA1 germline mutations are predisposed to breast and ovarian cancers. Accumulated evidence shows that BRCA1 is quickly recruited to DNA lesions and plays an important role in the DNA damage response. However, the mechanism by which BRCA1 is recruited to DNA damage sites remains elusive. BRCA1 forms a Ring-domain heterodimer with BARD1, a major partner of BRCA1 that contains tandem BRCA1 C-terminus (BRCT) motifs. Here, we identify the BRCTs of BARD1 as a poly(ADP-ribose) (PAR)-binding module. The binding of the BARD1 BRCTs to PAR targets the BRCA1/BARD1 heterodimer to DNA damage sites. Thus, our study uncovers a PAR-dependent mechanism of rapid recruitment of BRCA1/BARD1 to DNA damage sites.

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Biallelic ADPRHL2 mutations in complex neuropathy affect ADP ribosylation and DNA damage response.

Project description:ADP ribosylation is a reversible posttranslational modification mediated by poly(ADP-ribose)transferases (e.g., PARP1) and (ADP-ribosyl)hydrolases (e.g., ARH3 and PARG), ensuring synthesis and removal of mono-ADP-ribose or poly-ADP-ribose chains on protein substrates. Dysregulation of ADP ribosylation signaling has been associated with several neurodegenerative diseases, including Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Recessive ADPRHL2/ARH3 mutations are described to cause a stress-induced epileptic ataxia syndrome with developmental delay and axonal neuropathy (CONDSIAS). Here, we present two families with a neuropathy predominant disorder and homozygous mutations in ADPRHL2 We characterized a novel C26F mutation, demonstrating protein instability and reduced protein function. Characterization of the recurrent V335G mutant demonstrated mild loss of expression with retained enzymatic activity. Although the V335G mutation retains its mitochondrial localization, it has altered cytosolic/nuclear localization. This minimally affects basal ADP ribosylation but results in elevated nuclear ADP ribosylation during stress, demonstrating the vital role of ADP ribosylation reversal by ARH3 in DNA damage control.

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Poly(ADP-Ribose) Links the DNA Damage Response and Biomineralization.

Project description:Biomineralization of the extracellular matrix is an essential, regulated process. Inappropriate mineralization of bone and the vasculature has devastating effects on patient health, yet an integrated understanding of the chemical and cell biological processes that lead to mineral nucleation remains elusive. Here, we report that biomineralization of bone and the vasculature is associated with extracellular poly(ADP-ribose) synthesized by poly(ADP-ribose) polymerases in response to oxidative and/or DNA damage. We use ultrastructural methods to show poly(ADP-ribose) can form both calcified spherical particles, reminiscent of those found in vascular calcification, and biomimetically calcified collagen fibrils similar to bone. Importantly, inhibition of poly(ADP-ribose) biosynthesis in vitro and in vivo inhibits biomineralization, suggesting a therapeutic route for the treatment of vascular calcifications. We conclude that poly(ADP-ribose) plays a central chemical role in both pathological and physiological extracellular matrix calcification.

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Poly(ADP-Ribose) Mediates the BRCA2-Dependent Early DNA Damage Response.

Project description:Breast cancer susceptibility gene 2 (BRCA2) plays a key role in DNA damage repair for maintaining genomic stability. Previous studies have shown that BRCA2 contains three tandem oligonucleotide/oligosaccharide binding folds (OB-folds) that are involved in DNA binding during DNA double-strand break repair. However, the molecular mechanism of BRCA2 in DNA damage repair remains elusive. Unexpectedly, we found that the OB-folds of BRCA2 recognize poly(ADP-ribose) (PAR) and mediate the fast recruitment of BRCA2 to DNA lesions, which is suppressed by PARP inhibitor treatment. Cancer-associated mutations in the OB-folds of BRCA2 disrupt the interaction with PAR and abolish the fast relocation of BRCA2 to DNA lesions. The quickly recruited BRCA2 is important for the early recruitment of exonuclease 1(EXO1) and is involved in DNA end resection, the first step of homologous recombination (HR). Thus, these findings uncover a molecular mechanism by which BRCA2 participates in DNA damage repair.

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CTCF participates in DNA damage response via poly(ADP-ribosyl)ation.

Project description:CCCTC-binding factor (CTCF) plays an essential role in regulating the structure of chromatin by binding DNA strands for defining the boundary between active and heterochromatic DNA. However, the role of CTCF in DNA damage response remains elusive. Here, we show that CTCF is quickly recruited to the sites of DNA damage. The fast recruitment is mediated by the zinc finger domain and poly (ADP-ribose) (PAR). Further analyses show that only three zinc finger motifs are essential for PAR recognition. Moreover, CTCF-deficient cells are hypersensitive to genotoxic stress such as ionizing radiation (IR). Taken together, these results suggest that CTCF participate in DNA damage response via poly(ADP-ribosylation).

| S-EPMC5337984 | biostudies-literature

Serine is the major residue for ADP-ribosylation upon DNA damage.

Project description:Poly(ADP-ribose) polymerases (PARPs) are a family of enzymes that synthesise ADP-ribosylation (ADPr), a reversible modification of proteins that regulates many different cellular processes. Several mammalian PARPs are known to regulate the DNA damage response, but it is not clear which amino acids in proteins are the primary ADPr targets. Previously, we reported that ARH3 reverses the newly discovered type of ADPr (ADPr on serine residues; Ser-ADPr) and developed tools to analyse this modification (Fontana et al., 2017). Here, we show that Ser-ADPr represents the major fraction of ADPr synthesised after DNA damage in mammalian cells and that globally Ser-ADPr is dependent on HPF1, PARP1 and ARH3. In the absence of HPF1, glutamate/aspartate becomes the main target residues for ADPr. Furthermore, we describe a method for site-specific validation of serine ADP-ribosylated substrates in cells. Our study establishes serine as the primary form of ADPr in DNA damage signalling.

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The nucleosomal surface is the main target of histone ADP-ribosylation in response to DNA damage.

Project description:ADP-ribosylation is a protein post-translational modification catalyzed by ADP-ribose transferases (ARTs). ART activity is critical in mediating many cellular processes, and is required for DNA damage repair. All five histone proteins are extensively ADP-ribosylated by ARTs upon induction of DNA damage. However, how these modifications aid in repair processes is largely unknown, primarily due to lack of knowledge about where they site-specifically occur on histones. Here, we conduct a comprehensive analysis of histone Asp/Glu ADP-ribosylation sites upon DNA damage induced by dimethyl sulfate (DMS). We also demonstrate that incubation of cell nuclei with NAD+, as has been done previously in the literature, leads to spurious ADP-ribosylation levels of histone proteins. Altogether, we were able to identify 30 modification sites, 20 of which are novel. We also quantify the abundance of these modification sites during the course of DNA damage insult to identify which sites are critical for mediating repair. We found that every quantifiable site increases in abundance over time and that each identified ADP-ribosylation site is located on the surface of the nucleosome. Together, the data suggest specific Asp/Glu residues are unlikely to be critical for DNA damage repair and rather that this process is likely dependent on ADP-ribosylation of the nucleosomal surface in general.

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