The chromatin-associated enzyme poly(ADP-ribose) polymerase (ADPRT; EC 2.4.2.30 ) is a 116-kD protein that uses NAD as substrate to catalyze both the covalent transfer of ADP-ribose to a variety of nuclear protein acceptors and
subsequently the transfer of an additional 60 to 80 ADP-ribose units to the initial moiety. Nuclear proteins that become
predominantly poly(ADP-ribosyl)ated include nucleosomal core histones, histone H1 , HMG proteins , and topoisomerases I and II. ADP ribosyltransferase is required for cellular repair.
Inhibitors of this enzyme potentiate the lethal effects of noxious agents.
ADP-ribosylation is a eukaryotic posttranslational modification of proteins that is strongly induced by the presence of
DNA strand breaks and plays a role in DNA repair and the recovery of cells from DNA damage.
Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2. Doege CA et al. Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by using the pluripotency factors Oct4, Sox2, Klf4 and c-Myc (together referred to as OSKM). iPSC reprogramming erases somatic epigenetic signatures?as typified by DNA methylation or histone modification at silent pluripotency loci?and establishes alternative epigenetic marks of embryonic stem cells (ESCs). Here we describe an early and essential stage of somatic cell reprogramming, preceding the induction of transcription at endogenous pluripotency loci such as Nanog and Esrrb. By day 4 after transduction with OSKM, two epigenetic modification factors necessary for iPSC generation, namely poly(ADP-ribose) polymerase-1 (Parp1) and ten-eleven translocation-2 (Tet2), are recruited to the Nanog and Esrrb loci. These epigenetic modification factors seem to have complementary roles in the establishment of early epigenetic marks during somatic cell reprogramming: Parp1 functions in the regulation of 5-methylcytosine (5mC) modification, whereas Tet2 is essential for the early generation of 5-hydroxymethylcytosine (5hmC) by the oxidation of 5mC (refs 3,4). Although 5hmC has been proposed to serve primarily as an intermediate in 5mC demethylation to cytosine in certain contexts, our data, and also studies of Tet2-mutant human tumour cells, argue in favour of a role for 5hmC as an epigenetic mark distinct from 5mC. Consistent with this, Parp1 and Tet2 are each needed for the early establishment of histone modifications that typify an activated chromatin state at pluripotency loci, whereas Parp1 induction further promotes accessibility to the Oct4 reprogramming factor. These findings suggest that Parp1 and Tet2 contribute to an epigenetic program that directs subsequent transcriptional induction at pluripotency loci during somatic cell reprogramming.///////////The PARP inhibitor, olaparib, depletes the ovarian reserve in mice: implications for fertility preservation. Winship AL et al. (2020) What is the impact of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, alone or in combination with chemotherapy on the ovary in mice? Olaparib treatment, when administered alone, depletes primordial follicle oocytes, but olaparib does not exacerbate chemotherapy-mediated ovarian follicle loss in mice. The ovary contains a finite number of oocytes stored within primordial follicles, which give rise to all mature ovulatory oocytes. Unfortunately, they are highly sensitive to exogenous DNA damaging insults, such as cytotoxic cancer treatments. Members of the PARP family of enzymes are central to the repair of single-strand DNA breaks. PARP inhibitors have shown promising clinical efficacy in reducing tumour burden, by blocking DNA repair capacity. Olaparib is a PARP1/2 inhibitor recently FDA-approved for treatment of BRCA1 and BRCA2 mutation carriers with metastatic breast cancer. It is currently being investigated as an adjunct to standard treatment at an earlier stage, potentially curable, BRCA1- and BRCA2-associated breast cancer which affects reproductive age women. Despite this, there is no preclinical or clinical information regarding the potential impacts of olaparib on the ovary or on female fertility. Unfortunately, it may be many years before clinical data on fertility outcomes for women treated with PARP inhibitors becomes available, highlighting the importance of rigorous preclinical research using animal models to establish the potential for new cancer therapies to affect the ovary in humans. We aimed to comprehensively determine the impact of olaparib alone, or following chemotherapy, on the ovary in mice. On Day 0, mice (n = 5/treatment group) were administered a single intraperitoneal dose of cyclophosphamide (75 mg/kg/body weight), doxorubicin (10 mg/kg), carboplatin (80 mg/kg), paclitaxel (7.5 mg/kg) or vehicle control. From Days 1 to 28, mice were administered subcutaneous olaparib (50 mg/kg) or vehicle control. This regimen is proven to reduce tumour burden in preclinical mouse studies and is also physiologically relevant for women. Adult female wild-type C57BL6/J mice at peak fertility (8 weeks) were administered a single intraperitoneal dose of chemotherapy, or vehicle, then either subcutaneous olaparib or vehicle for 28 days. Vaginal smears were performed on each animal for 14 consecutive days from Days 15 to 28 to monitor oestrous cycling. At 24 h after final treatment, ovaries were harvested for follicle enumeration and immunohistochemical analysis of primordial follicle remnants (FOXL2 expressing granulosa cells), DNA damage (γH2AX) and analysis of apoptosis by TUNEL assay. Serum was collected to measure circulating anti-Müllerian hormone (AMH) concentrations by ELISA. Olaparib significantly depleted primordial follicles by 36% compared to the control (P < 0.05) but had no impact on other follicle classes, serum AMH, corpora lutea number (indicative of ovulation) or oestrous cycling. Primordial follicle remnants were rarely detected in control ovaries but were significantly elevated in ovaries from mice treated with olaparib alone (P < 0.05). Similarly, DNA damage denoted by γH2AX foci was completely undetectable in primordial follicles of control animals but was observed in ∼10% of surviving primordial follicle oocytes in mice treated with olaparib alone. These observations suggest that functional PARPs are essential for primordial follicle oocyte maintenance and survival. Olaparib did not exacerbate chemotherapy-mediated follicle depletion in the wild-type mouse ovary. N/A. This study was performed in mice, so the findings may not translate to women and further studies utilizing human ovarian tissue and sera samples should be performed in the future. Only one long-term time point was analysed, therefore olaparib-mediated follicle damage should be assessed at more immediate time points in the future to support our mechanistic findings. Olaparib dramatically depleted primordial follicles and this could be attributed to loss of intrinsic PARP-mediated DNA repair mechanisms. Importantly, diminished ovarian reserve can result in premature ovarian insufficiency and infertility. Notably, the extent of follicle depletion might be enhanced in BRCA1 and BRCA2 mutation carriers, and this is the subject of current investigations. Together, our data suggest that fertility preservation options should be considered for young women prior to olaparib treatment, and that human studies of this issue should be prioritized. This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. This work was supported by funding from the National Health and Medical Research Council (NHMRC); (K.J.H. #1050130) (A.L.W. #1120300). K.A.P. is a National Breast Cancer Foundation Fellow (Australia-PRAC-17-004). K.A.P. is the Breast Cancer Trials (Australia) Study Chair for the OlympiA clinical trial sponsored by AstraZeneca, the manufacturer of olaparib. All other authors declare no competing financial or other interests.//////////////////
NCBI Summary:
This gene encodes a chromatin-associated enzyme, poly(ADP-ribosyl)transferase, which modifies various nuclear proteins by poly(ADP-ribosyl)ation. The modification is dependent on DNA and is involved in the regulation of various important cellular processes such as differentiation, proliferation, and tumor transformation and also in the regulation of the molecular events involved in the recovery of cell from DNA damage. In addition, this enzyme may be the site of mutation in Fanconi anemia, and may participate in the pathophysiology of type I diabetes. [provided by RefSeq, Jul 2008]
General function
Cell death/survival, Anti-apoptotic, DNA Replication, Enzyme, Transferase
, Epigenetic modifications
Comment
Parp1 deficiency confers defects in chromatin surveillance and remodeling during reprogramming by nuclear transfer. Osada T et al. (2016) Accumulating evidence suggests that cloned mice production by the injection of a somatic cell nucleus into an enucleated oocyte is inefficient. DNA damage and chromatin remodeling failures that occur during embryogenesis following nuclear transfer (NT) might explain the poor development of cloned embryos. To avoid these problems, it is important to elucidate somatic chromatin remodeling after NT. Because polyADP-ribosylation, which is catalyzed mainly by poly(ADP-ribose) polymerase 1 (Parp1), is a major post-translational modification that facilitates DNA repair and chromatin remodeling, we examined the effects of Parp1 deficiency in developing NT embryos. Parp1 was located within the pseudo-pronuclei (PPN) of NT eggs. We observed that NT eggs, after activation by Sr2+, formed PPN with significantly more efficiency in Parp1-null embryos than in wild-type NT embryos. However, most the Parp1-null embryos stopped developing by the four-cell stage. Immunostaining for γH2AX foci, a marker of DNA double strand breaks, showed longer retention in the PPN of Parp1-/- donor NT embryos than in wild-type NT embryos, suggesting that, in the absence of Parp1, DNA breaks are slowly repaired and consequently, entry into the S phase might be delayed. Furthermore, decreases in histone H3 acetylation, H3 monomethylation at lysine 4, and H3 trimethylation at lysine 27 after the Sr2+ activation step were observed in the PPN of Parp1-/- donor embryos. Taken together, our data suggest that Parp1 is involved in the plastic remodeling of chromatin structure after NT by supporting DNA repair and specific histone code modifications.//////////////////
Cellular localization
Nuclear
Comment
Poly (ADP-ribose) polymerase inhibitor exposure reduces ovarian reserve followed by dysfunction in granulosa cells. Nakamura K et al. (2020) The use of poly (ADP-ribose) polymerase (PARP) inhibitors is expected to increase, but their effect on fertility is still unclear. The aim of this study was to investigate the effect of PARP inhibitors on ovarian function. In an in vitro study, cultures of ovaries and granulosa cells (GCs) exposed to the PARP inhibitor olaparib were evaluated by real-time RT-PCR, histological study, and hormone assays. In an in vivo study, mice were administered olaparib orally and evaluated via in vitro fertilization (IVF), follicle count, immunohistochemical staining, and real-time RT-PCR. In vitro, the gene expression of GC markers decreased in the olaparib-treated group. Olaparib also negatively affected estradiol production and the expression of GC markers in cultured GCs, with abnormal morphology of GCs observed in the treated group. The follicle number indicated depletion of follicles due to atretic changes in the treatment group, both in vitro and in vivo. Also, olaparib reduced the number of retrieved oocytes and the fertilization rate of IVF, but they recovered after 3 weeks of cessation. Our results indicate that olaparib is toxic to ovaries.//////////////////
Ovarian function
Cumulus expansion, Follicle atresia, Luteolysis, Oocyte maturation, Early embryo development
Comment
Roles of poly (ADP-ribose) polymerase 1 activation and cleavage in induction of multi-oocyte ovarian follicles in the mouse by 3-nitropropionic acid. Wei Q et al. (2019) 3-nitropropionic acid (3-NPA) is known to be a mitochondrial toxin produced by plants and fungi, which may produce DNA damage in cells. However, studies of its reproductive toxicology are lacking. We know that poly(ADP-ribose) polymerase (PARP) plays an important role in a large variety of physiological processes and is involved in DNA repair pathways. The present study was therefore aimed at exploring the involvement of PARP-1 activation and cleavage after 3-NPA stimulation in female mice. We observed an increased number of atretic follicles and multi-oocyte follicles (MOFs) after treatment with 3-NPA and serum concentrations of 17β-oestradiol and progesterone were significantly reduced. Our results provide evidence that PARP-1 cleavage and activational signals are involved in pathological ovarian processes stimulated by 3-NPA. In addition, total superoxide dismutase, glutathione peroxidase and catalase activities were significantly increased, whereas succinate dehydrogenase was decreased in a dose-dependent manner. Results from our in vitro study similarly indicated that 3-NPA inhibited the proliferation of mouse granulosa cells and increased apoptosis in a dose-dependent manner. In summary, 3-NPA induces granulosa cell apoptosis, follicle atresia and MOFs in the ovaries of female mice and causes oxidative stress so as to disrupt endogenous hormonal systems, possibly acting through PARP-1 signalling.//////////////////
MicroRNA-379-5p is associate with biochemical premature ovarian insufficiency through PARP1 and XRCC6. Dang Y et al. (2018) Premature ovarian insufficiency (POI) imposes great challenges on women's fertility and lifelong health. POI is highly heterogeneous and encompasses occult, biochemical, and overt stages. MicroRNAs (miRNAs) are negative regulators of gene expression, whose roles in physiology and diseases like cancers and neurological disorders have been recognized, but little is known about the miRNAs profile and functional relevance in biochemical POI (bPOI). In this study, the expression of miRNAs and mRNAs in granulosa cells (GCs) of bPOI women was determined by two microarrays, respectively. MiR-379-5p, PARP1, and XRCC6 were differentially expressed in GCs of bPOI as revealed by microarrays. Subsequently, functional studies demonstrated that miR-379-5p overexpression inhibited granulosa cell proliferation and attenuated DNA repair efficiency. Furthermore, both PARP1 and XRCC6 showed lower levels in GCs from patients with bPOI and were identified as executives of miR-379-5p. Therefore, our data first uncovered potentially pathogenic miR-379-5p and two novel targets PARP1 and XRCC6 in bPOI, which corroborated the significance of DNA repair for POI, and brought up an epigenetic explanation for the disease.//////////////////
The effect of poly(ADP-ribosyl)ation inhibition on the porcine cumulus-oocyte complex during in vitro maturation. Kim DH et al. (2016) Poly(ADP-ribosyl)ation (PARylation) plays important roles in DNA repair, apoptosis, transcriptional regulation, and cell death, and occurs via the activity of poly(ADP-ribose) polymerases (PARPs). Previous studies have shown that PARylation affects mouse and porcine pre-implantation development and participates in mechanisms of autophagy. However, there have not yet been reported the role of PARylation during in vitro maturation (IVM) of porcine oocytes. Thus, we investigated the effect of PARylation inhibition on this process; cumulus-oocyte complexes (COCs) were cultured with 3-aminobenzamide (3-ABA, PARP inhibitor) during porcine IVM. Full cumulus expansion was significantly reduced (10.34 ± 1.23 3-ABA] vs. 48.17 ± 2.03% [control]), but nuclear maturation rates were not changed in the 3-ABA treatment group. Especially, we observed that cumulus cells were little expanded after 22 h in 3-ABA treated COCs. The mRNA expression levels of oocyte maturation- and cumulus expansion-related genes were evaluated at 22 and 44 h. GDF9, BMP15, COX-2, and PTX3 expression were upregulated at 44 h, whereas the levels of HAS2 and TNFAIP6 were downregulated in the 3-ABA treated group. Furthermore, 3-ABA treatment significantly decreased the developmental rate (28.24 ± 1.06 vs. 40.24 ± 3.03%) and total cell number (41.12 ± 2.10 vs. 50.38 ± 2.27), but increased the total apoptotic index (6.44 ± 0.81 vs. 3.08 ± 0.51) in parthenogenetically activated embryos. In conclusion, these results showed that PARylation regulates cumulus expansion through the regulation of gene expression and affects developmental competence and quality in parthenogenetic embryos.//////////////////
Roles of poly (ADP-ribose) polymerase (PARP-1) cleavage in the ovaries of fetal, neonatal and adult pigs. [Wei Q 2013 et al.
Poly (ADP-ribosylation), which occurs rapidly in cells following DNA damage and is regulated by poly (ADP-ribose) polymerase-1 (PARP-1), is a post-translational modi?cation of proteins playing a crucial role in many processes, including DNA repair and cell death. Although PARP-1 has recently been implicated in a variety of physiological and pathological processes, its role in the process of follicular development and atresia is not yet completely defined. The present study was designed to investigate the cellular expression pattern and immunolocalization of PARP-1, cleaved PARP-1, caspase-3 and cleaved caspase-3 in fetal, neonatal and adult porcine ovaries. Our results showed that in fetal and neonatal pigs, PARP-1 cleavage is involved in the process of oocyte nest breakdown, primordial follicle formation and transition to primary follicles. The results of immunohistochemistry indicated that PARP-1 cleavage was involved in the process follicular development and atresia, which was in accordance with our previous study; however, it was noted that cleaved caspase-3 was mainly localized in and around the nucleus of apoptotic granulosa cells, whereas cleaved PARP-1 was mainly localized in the nucleus of the apoptotic granulosa cells. Radioimmunoassay (RIA) data showed that incresed serum concentrations of progesterone (P4) and estradiol (E2) with age after birth. Collectively, our findings suggest that the PARP-1 signaling pathway is involved in oocyte nest breakdown and primordial follicle formation in fetal and neonatal porcine ovaries, but is different from follicular atresia in adult porcine ovaries that involves cellular apoptosis.
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of poly (ADP-ribose) polymerase-1 is involved in the process of porcine ovarian follicular atresia. Wei Q et al. Ovarian follicle atresia is a common phenomenon in vertebrate ovaries and this process is characterized by follicular wall degeneration. The molecular mechanism underlying follicle atresia is apoptotic granulusa cell death; however, the exact signaling pathway is still unclear. PARP-1, the founding member of the poly (ADP-ribose) polymerase (PARP) family, plays an important role in a large variety of physiological processes. Although its cleavage has recently been implicated in a variety of physiological and pathological processes, its role in the process of follicular atresia is not yet completely defined. We identified the cleavage of PARP-1 involved in the process of follicle degeneration, which is known as 'follicular atresia', both from in vivo models and cell culture data. The results from immunohistochemistry (IHC) showed that cleaved PARP-1 was mainly located in apoptotic granulosa cells (GCs); and the expression of PARP-1 and caspase-3 were decreased in apoptotic granulosa cells (GCs). The results from western blotting showed that PARP-1 expression was significantly decreased in atretic follicles compared with healthy (H) follicles, and the cleavage of caspase-3 (17kDa) significantly increased in atretic follicles. Along with the cleavage of caspase-3, the expression of cleaved PARP-1 (24kDa) product was significantly increased, which confirmed caspase-3 activation. Serum starvation led to a reduction in PARP-1 and an increase in cleaved PARP-1 (24kDa) and caspase-3 (17kDa), suggesting that caspase-3 was activated under the stress of withdrawal of growth factors, in accordance with the in vivo study. In the present study, the concentrations of estradiol (E2) and progesterone (P4) as well as the P4/E2 (P/E) ratio were combined with morphological features to determine follicular classification. In summary, the present study demonstrated that cleavage of PARP-1 by caspase-3 was involved in the process of granulosa cell apoptosis. PARP-1 may through its cleavage act as a critical regulator in the process of porcine follicular atresia. Our results identified that cleavage of PARP-1 by activated (cleaved) caspase-3 may serve a key role in controlling follicular atresia through granulosa cell degeneration. These findings should prove helpful in understanding the regulatory mechanisms controlling follicular development and atresia.
Poly(ADP-ribose) polymerase inhibitor, 3-aminobenzamide, protects against experimental immune ovarian failure in mice. Makogon N et al. The activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) may play an important role in numerous pathological conditions. The aim of the present study was to clarify the role of PARP in the pathogenesis of immune ovarian failure in mice and to examine the possible protective action of PARP inhibitor, 3-aminobenzamide (3-ABA). An experimental ovarian injury induced in mice by immunization with allogenic ovarian extract impaired the meiotic maturation of oocytes and increased apoptosis and necrosis of follicular cells and cells isolated from the spleen, lymph nodes and thymus. The immunization affected blood leukogram indicating the presence of an inflammatory response. Treatment with 3-ABA (1 h before antigen administrations, 0.02 mg/g intraperitoneally, twice a week during the three-week experiment) was effective to prevent meiotic maturation impairment, cell death and inflammation. The decrease in the necrosis of follicular and immune cells after 3-ABA treatment was more pronounced than that in apoptosis. It is concluded that PARP may contribute to immune-mediated ovary injury and PARP inhibitor, 3-ABA, protects against experimental immune ovarian failure, partially via a decrease in necrotic cell death.
Oocyte Numbers in the Mouse Increase after Treatment with 5-Aminoisoquinolinone: A Potent Inhibitor of Poly(ADP-ribosyl)ation. Qian H et al. Poly(ADP-ribosyla)tion is a post-translational protein modification carried out by a family of enzymes referred to as poly(ADP-ribose) polymerases (PARPs). It has been proposed that the broad nuclear distribution of PARPs may allow them to modulate gene expression in addition to their more accepted role as DNA repair mediators. The role of poly(ADP-ribosyl)ation during oogenesis and folliculogenesis is unknown. Here we found that when 3- to 4-wk-old mice were injected with 5-amninoisoquinolinone, a water soluble inhibitor of poly(ADP-ribosyl)ation, it lead to considerably increased oocyte numbers and a dramatic increase in primordial follicle numbers. Furthermore, we show that inhibition of poly(ADP)ribosylation leads to an increased expression of specific genes and pathways in mouse ovaries, in particular TGF superfamily members. Our results demonstrate that poly(ADP-ribosyl)ation, is a key player in oogenesis and folliculogenesis and it may have a differential role in regulating gene expression, DNA repair and apoptosis. The novel function of poly(ADP-ribosyl)ation in oogenesis and folliculogenesis sheds light on the alternative role that DNA repair mediators may play in cellular development and differentiation.
Khan SM, et al 2000 studied the role of mitochondria and caspases in induced apoptosis in human
luteinized granulosa cells
Luteinized granulosa cells isolated from in
vitro fertilization patients were treated with staurosporine. Microscopy
revealed that staurosporine treatment resulted in cells exhibiting evidence of
apoptosis, including cell detachment, loss of cell processes, membrane
shrinkage, and formation of apoptotic bodies.
Western analysis showed cleavage of a caspase substrate, poly-(ADP-ribose)-polymerase (PARP)
in staurosporine-treated cells.
Expression regulated by
Steroids
Comment
Ovarian localization
Oocyte, Granulosa, Surface epithelium
Comment
Persistence of histone H2AX phosphorylation after meiotic chromosome synapsis and abnormal centromere cohesion in Poly (ADP-ribose) polymerase (Parp-1) null oocytes. Yang F et al. In spite of the impact of aneuploidy on human health little is known concerning the molecular mechanisms involved in the formation of structural or numerical chromosome abnormalities during meiosis. Here, we provide novel evidence indicating that lack of PARP-1 function during oogenesis predisposes the female gamete to genome instability. During prophase I of meiosis, a high proportion of Parp-1((-/-)) mouse oocytes exhibit a spectrum of meiotic defects including incomplete homologous chromosome synapsis or persistent histone H2AX phosphorylation in fully synapsed chromosomes at the late pachytene stage. Moreover, the X chromosome bivalent is also prone to exhibit persistent double strand DNA breaks (DSBs). In striking contrast, such defects were not detected in mutant pachytene spermatocytes. In fully-grown wild type oocytes at the germinal vesicle stage, PARP-1 protein associates with nuclear speckles and upon meiotic resumption, undergoes a striking re-localization towards spindle poles as well as pericentric heterochromatin domains at the metaphase II stage. Notably, a high proportion of in vivo matured Parp-1((-/-)) oocytes show lack of recruitment of the kinetochore-associated protein BUB3 to centromeric domains and fail to maintain metaphase II arrest. Defects in chromatin modifications in the form of persistent histone H2AX phosphorylation during prophase I of meiosis and deficient sister chromatid cohesion during metaphase II predispose mutant oocytes to premature anaphase II onset upon removal from the oviductal environment. Our results indicate that PARP-1 plays a critical role in the maintenance of chromosome stability at key stages of meiosis in the female germ line. Moreover, in the metaphase II stage oocyte PARP-1 is required for the regulation of centromere structure and function through a mechanism that involves the recruitment of BUB3 protein to centromeric domains.
Murdoch WJ studied the perturbation of sheep ovarian surface epithelial cells by
ovulation and provided evidence for roles of progesterone and
poly(ADP-ribose) polymerase in the restoration of DNA integrity.
He suggested that
DNA damage to ovarian surface epithelium that is inflicted at ovulation is
(normally) reconciled on a localized basis by progesterone/PARP-mediated
repair or dedicated apoptotic cell death thereby conferring protection against
clonal transformation.
Follicle stages
Antral
Comment
Phenotypes
Mutations
3 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: fertile Comment:dAdda di Fagagna et al. (1999) showed that mice lacking PARP display telomere
shortening compared with wildtype mice. Telomere shortening was seen in different genetic backgrounds and in
different tissues from embryos and adult mice. In vitro telomerase activity, however, was not altered in Adprt1 -/-
mouse fibroblasts. Furthermore, cytogenetic analysis of mouse embryonic fibroblasts showed that lack of PARP was
associated with severe chromosomal instability, characterized by increased frequency of chromosome fusions and
aneuploidy. The absence of PARP does not affect the presence of single-strand overhangs, naturally present at the end
of telomeres.
Species: mouse
Mutation name: type: null mutation fertility: subfertile Comment: Persistence of histone H2AX phosphorylation after meiotic chromosome synapsis and abnormal centromere cohesion in poly (ADP-ribose) polymerase (Parp-1) null oocytes. Yang F et al. (2009) In spite of the impact of aneuploidy on human health little is known concerning the molecular mechanisms involved in the formation of structural or numerical chromosome abnormalities during meiosis. Here, we provide novel evidence indicating that lack of PARP-1 function during oogenesis predisposes the female gamete to genome instability. During prophase I of meiosis, a high proportion of Parp-1((-/-)) mouse oocytes exhibit a spectrum of meiotic defects including incomplete homologous chromosome synapsis or persistent histone H2AX phosphorylation in fully synapsed chromosomes at the late pachytene stage. Moreover, the X chromosome bivalent is also prone to exhibit persistent double strand DNA breaks (DSBs). In striking contrast, such defects were not detected in mutant pachytene spermatocytes. In fully-grown wild type oocytes at the germinal vesicle stage, PARP-1 protein associates with nuclear speckles and upon meiotic resumption, undergoes a striking re-localization towards spindle poles as well as pericentric heterochromatin domains at the metaphase II stage. Notably, a high proportion of in vivo matured Parp-1((-/-)) oocytes show lack of recruitment of the kinetochore-associated protein BUB3 to centromeric domains and fail to maintain metaphase II arrest. Defects in chromatin modifications in the form of persistent histone H2AX phosphorylation during prophase I of meiosis and deficient sister chromatid cohesion during metaphase II predispose mutant oocytes to premature anaphase II onset upon removal from the oviductal environment. Our results indicate that PARP-1 plays a critical role in the maintenance of chromosome stability at key stages of meiosis in the female germ line. Moreover, in the metaphase II stage oocyte PARP-1 is required for the regulation of centromere structure and function through a mechanism that involves the recruitment of BUB3 protein to centromeric domains.//////////////////
Species: mouse
Mutation name: type: null mutation fertility: unknown Comment: Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes. Pieper AA et al. (1999) Streptozotocin (STZ) selectively destroys insulin-producing beta islet cells of the pancreas providing a model of type I diabetes. Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme whose overactivation by DNA strand breaks depletes its substrate NAD+ and then ATP, leading to cellular death from energy depletion. We demonstrate DNA damage and a major activation of PARP in pancreatic islets of STZ-treated mice. These mice display a 500% increase in blood glucose and major pancreatic islet damage. In mice with homozygous targeted deletion of PARP (PARP -/-), blood glucose and pancreatic islet structure are normal, indicating virtually total protection from STZ diabetes. Partial protection occurs in PARP +/- animals. Thus, PARP activation may participate in the pathophysiology of type I diabetes, for which PARP inhibitors might afford therapeutic benefit.//////////////////