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Epigenetic Modifications of Histones
Published in Cristina Camprubí, Joan Blanco, Epigenetics and Assisted Reproduction, 2018
George Rasti, Alejandro Vaquero
ADP-ribosylation (ADPR) involves the addition of the ADP-ribose moiety of NAD+. Some members of the PARP superfamily have been shown to promote mono- or poly-ADPR of histones. The levels of poly ADP-ribosylation, PARP-1, and PARP-2 catalytic activity (14), and the turnover of ADP-ribosyl residues all decreased during the differentiation of the germinal cell line, most noticeably at the end of spermiogenesis, which suggests a possible role for this modification in male fertility (15).
Irradiation-induced damage and the DNA damage response
Published in Michael C. Joiner, Albert J. van der Kogel, Basic Clinical Radiobiology, 2018
Conchita Vens, Marianne Koritzinsky, Bradly G. Wouters
The nature of the lesion dictates the presence of the initial damage-sensing protein. For example, base lesions are recognized by specific glycosylases that are designed to identify and remove the damaged base, while the loss of bases or phosphodiester bonds within DNA quickly activates poly (ADP-ribosylation)-polymerases (PARPs). DSBs are recognized by the MRN complex, consisting of three proteins: MRE11, RAD50 and NBS1. Notably, the NBS1 protein is the product of the gene that is mutated in Nijmegen breakage syndrome (NBS). As its central function in DSB recognition and repair suggests, patients with this syndrome are radiosensitive. The Ku proteins (Ku70 and 80) can also recognize and efficiently bind the ends of DSBs. Single-stranded DNA regions generated during replication or during DSBR are coated by the RPA complex. These initial DNA damage sensing events influence repair pathway choice and dictate DDR signalling through engaging different signal transduction proteins and mechanisms.
Poly (ADP-Ribose) Polymerase — A Nonhistone Nuclear Protein
Published in Lubomir S. Hnilica, Chromosomal Nonhistone Proteins, 2018
Considerable progress has been made in cataloging the acceptor proteins for poly ADP-ribosylation and in characterizing the linkage of (ADP-ribose) to these acceptors. Both in vivo as well as in vitro studies have indicated that histones as well as nonhistone chromosomal proteins are ADP-ribosylated.
Poly (ADP-ribose) polymerase (PARP) as target for the treatment of epithelial ovarian cancer: what to know
Published in Expert Opinion on Investigational Drugs, 2021
Luigi Della Corte, Virginia Foreste, Claudia, Di Filippo, Pierluigi Giampaolino, Giuseppe Bifulco
The PARPs family share the ability to catalyze the transfer of ADP-ribose to target proteins (poly ADP-ribosylation) [34]. Several cellular substrates for PARP have been defined, and a majority of these proteins are nuclear proteins that are involved in nucleic acid metabolism, modulation of chromatin structure, DNA synthesis, and DNA repair [35]. PARP1 is the first and best-characterized member of the PARP family, while PARP2 has 69% similarity to PARP1 in its catalytic domain, and was identified based on the persistence of PARP activity in PARP1-deficient cells [36]. PARP-1 has a molecular weight of 113 kDa and consists of three major domains [37]: the DNA-binding domain which includes two zinc-finger motifs that bind to DNA breaks thus triggering enzyme activation, a centrally located 16 kDa auto-modification domain which contains conserved glutamate and lysine residues, the targets for auto-poly (ADP-ribosyl)ation, and the 55 kDa C-terminal catalytic domain, the region targeted by the majority of drug discovery programs [38].
Defining and targeting wild-type BRCA high-grade serous ovarian cancer: DNA repair and cell cycle checkpoints
Published in Expert Opinion on Investigational Drugs, 2019
S. Percy Ivy, Charles A. Kunos, Fernanda I. Arnaldez, Elise C. Kohn
Poly(ADP-ribosylation), also known as parylation, is a post-translational alteration by which polymers of ADP-ribose are covalently attached to intracellular proteins by PARPs. PARP inhibition can result in cell death in the presence of an existing DNA repair defect – a prime example of clinical synthetic lethality. There are 17 members of the PARP family; however, PARP1 (gene name PARP1) represents 90% of the intracellular content. PARP inhibition results in accumulation of double-stranded DNA breaks (Figure 1). Ovarian cancer cells with repair defects cannot undergo effective homologous recombination [30]. While this is the most accepted and studied mechanism, there is increasing evidence that PARP inhibitors can be toxic by forming complexes with DNA, in a process known as PARP trapping, to inhibit repair and limit the ability of cells to repair replication stress. Based on this scientific rationale, the safety and efficacy have been evaluated in several studies of persistent or recurrent ovarian cancer.
The development of PARP as a successful target for cancer therapy
Published in Expert Review of Anticancer Therapy, 2018
Roberto Ferrara, Francesca Simionato, Chiara Ciccarese, Elisabetta Grego, Sara Cingarlini, Roberto Iacovelli, Emilio Bria, Giampaolo Tortora, Davide Melisi
Besides its canonical role in DNA repairing systems, PARP has demonstrated broader functions in controlling cell survival and death [43], in modulating key components of angiogenesis (i.e. HIF 1-α) [44], and inflammatory response (i.e. NF-kB) [45] and in the regulation of a senescence associated secretory phenotype in cancer cells [46]. Interestingly, PARP may regulate immune responses, modulating the differentiation of regulatory T lymphocytes [47] and the production of Th1/Th2 cytokines by activated T-cells [48], in this regard, PARP inhibition ameliorates immune mediated diseases in several experimental models [47]. An additional DNA repair independent function of PARP1 relates to the safeguard of mitotic fidelity checkpoints, through the Poly (ADP) ribosylation of centrosomal proteins, which consent an accurate attachment of chromosomes to the microtubule based mitotic spindle. In this perspective, PARPi have been proposed in combinatorial regimens to selectively kill cancer cells resistant to microtubule stabilizing agents [49].