PARP-1 Activation Directs FUS to DNA Damage Sites to Form PARG-Reversible Compartments Enriched in Damaged DNA

Poly-ADP ribose polymerase 1 (PARP-1) is activated by DNA damage and has been implicated in the repair of single-strand breaks (SSBs). Involvement of PARP-1 in other DNA damage responses remains controversial. In this study, we show that PARP-1 is required for replication fork slowing on damaged DNA. Fork progression in PARP-1−/− DT40 cells is not slowed down even in the presence of DNA damage induced by the topoisomerase I inhibitor camptothecin (CPT). Mammalian cells treated with a PARP inhibitor or PARP-1–specific small interfering RNAs show similar results. The expression of human PARP-1 restores fork slowing in PARP-1−/− DT40 cells. PARP-1 affects SSB repair, homologous recombination (HR), and nonhomologous end joining; therefore, we analyzed the effect of CPT on DT40 clones deficient in these pathways. We find that fork slowing is correlated with the proficiency of HR-mediated repair. Our data support the presence of a novel checkpoint pathway in which the initiation of HR but not DNA damage delays the fork progression.

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Faculty Opinions recommendation of Structural basis for DNA damage-dependent poly(ADP-ribosyl)ation by human PARP-1.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.716397802.793465120 ◽

2012 ◽

Author(s):

Zucai Suo

Keyword(s):

Dna Damage ◽

Structural Basis ◽

Parp 1

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DNase II mediates a parthanatos-like developmental cell death pathway in Drosophila primordial germ cells

Nature Communications ◽

10.1038/s41467-021-22622-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Lama Tarayrah-Ibraheim ◽

Elital Chass Maurice ◽

Guy Hadary ◽

Sharon Ben-Hur ◽

Alina Kolpakova ◽

...

Keyword(s):

Dna Damage ◽

Cell Death ◽

Germ Cells ◽

Nuclear Translocation ◽

Primordial Germ Cells ◽

Nuclear Accumulation ◽

Dependent Manner ◽

Dnase Ii ◽

Cell Death Pathway ◽

Parp 1

AbstractDuring Drosophila embryonic development, cell death eliminates 30% of the primordial germ cells (PGCs). Inhibiting apoptosis does not prevent PGC death, suggesting a divergence from the conventional apoptotic program. Here, we demonstrate that PGCs normally activate an intrinsic alternative cell death (ACD) pathway mediated by DNase II release from lysosomes, leading to nuclear translocation and subsequent DNA double-strand breaks (DSBs). DSBs activate the DNA damage-sensing enzyme, Poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) and the ATR/Chk1 branch of the DNA damage response. PARP-1 and DNase II engage in a positive feedback amplification loop mediated by the release of PAR polymers from the nucleus and the nuclear accumulation of DNase II in an AIF- and CypA-dependent manner, ultimately resulting in PGC death. Given the anatomical and molecular similarities with an ACD pathway called parthanatos, these findings reveal a parthanatos-like cell death pathway active during Drosophila development.

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Impact of copper on the induction and repair of oxidative DNA damage, poly(ADP-ribosyl)ation and PARP-1 activity

Molecular Nutrition & Food Research ◽

10.1002/mnfr.200600107 ◽

2007 ◽

Vol 51 (2) ◽

pp. 201-210 ◽

Cited By ~ 24

Author(s):

Tanja Schwerdtle ◽

Ingrit Hamann ◽

Gunnar Jahnke ◽

Ingo Walter ◽

Constanze Richter ◽

...

Keyword(s):

Dna Damage ◽

Oxidative Dna Damage ◽

Parp 1

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Poly(ADP-ribose) polymerase-1 gene ablation protects mice from ischemic renal injury

AJP Renal Physiology ◽

10.1152/ajprenal.00436.2003 ◽

2005 ◽

Vol 288 (2) ◽

pp. F387-F398 ◽

Cited By ~ 66

Author(s):

Jianfeng Zheng ◽

Kishor Devalaraja-Narashimha ◽

Kurinji Singaravelu ◽

Babu J. Padanilam

Keyword(s):

Dna Damage ◽

Cell Death ◽

Mouse Model ◽

Renal Injury ◽

Atp Depletion ◽

Inflammatory Cascade ◽

Renal Functions ◽

Atp Levels ◽

Ischemic Renal Injury ◽

Parp 1

Increased generation of reactive oxygen species (ROS) and the subsequent DNA damage and excessive activation of poly(ADP-ribose) polymerase-1 (PARP-1) have been implicated in the pathogenesis of ischemic injury. We previously demonstrated that pharmacological inhibition of PARP protects against ischemic renal injury (IRI) in rats (Martin DR, Lewington AJ, Hammerman MR, and Padanilam BJ. Am J Physiol Regul Integr Comp Physiol 279: R1834–R1840, 2000). To further define the role of PARP-1 in IRI, we tested whether genetic ablation of PARP-1 attenuates tissue injury after renal ischemia. Twenty-four hours after reperfusion following 37 min of bilateral renal pedicle occlusion, the effects of the injury on renal functions in PARP−/− and PARP+/+ mice were assessed by determining glomerular filtration rate (GFR) and the plasma levels of creatinine. The levels of plasma creatinine were decreased and GFR was augmented in PARP−/− mice. Morphological evaluation of the kidney tissues showed that the extent of damage due to the injury in PARP−/− mice was less compared with their wild-type counterparts. The levels of ROS and DNA damage were comparable in the injured kidneys of PARP+/+ and PARP−/− mice. PARP activity was induced in ischemic kidneys of PARP+/+ mice at 6–24 h postinjury. At 6, 12, and 24 h after injury, ATP levels in the PARP+/+ mice kidney declined to 28, 26, and 43%, respectively, whereas it was preserved close to normal levels in PARP−/− mice. The inflammatory cascade was attenuated in PARP−/− mice as evidenced by decreased neutrophil infiltration and attenuated expression of inflammatory molecules such as TNF-α, IL-1β, and intercellular adhesion molecule-1. At 12 h postinjury, no apoptotic cell death was observed in PARP−/− mice kidneys. However, by 24 h postinjury, a comparable number of cells underwent apoptosis in both PARP−/− and PARP+/+ mice kidneys. Thus activation of PARP post-IRI contributes to cell death most likely by ATP depletion and augmentation of the inflammatory cascade in the mouse model. PARP ablation preserved ATP levels, renal functions, and attenuated inflammatory response in the setting of IRI in the mouse model. PARP inhibition may have clinical efficacy in preventing the progression of acute renal failure complications.

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SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome

Nature Communications ◽

10.1038/s41467-021-24391-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Federica Banfi ◽

Alicia Rubio ◽

Mattia Zaghi ◽

Luca Massimino ◽

Giulia Fagnocchi ◽

...

Keyword(s):

Dna Damage ◽

Neuronal Death ◽

Neuronal Loss ◽

Genotoxic Stress ◽

Protein Product ◽

Neural Progenitors ◽

Cell Identity ◽

Neurodegenerative Process ◽

Parp 1 ◽

Shed Light

AbstractThe investigation of genetic forms of juvenile neurodegeneration could shed light on the causative mechanisms of neuronal loss. Schinzel-Giedion syndrome (SGS) is a fatal developmental syndrome caused by mutations in the SETBP1 gene, inducing the accumulation of its protein product. SGS features multi-organ involvement with severe intellectual and physical deficits due, at least in part, to early neurodegeneration. Here we introduce a human SGS model that displays disease-relevant phenotypes. We show that SGS neural progenitors exhibit aberrant proliferation, deregulation of oncogenes and suppressors, unresolved DNA damage, and resistance to apoptosis. Mechanistically, we demonstrate that high SETBP1 levels inhibit P53 function through the stabilization of SET, which in turn hinders P53 acetylation. We find that the inheritance of unresolved DNA damage in SGS neurons triggers the neurodegenerative process that can be alleviated either by PARP-1 inhibition or by NAD + supplementation. These results implicate that neuronal death in SGS originates from developmental alterations mainly in safeguarding cell identity and homeostasis.

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Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice

Blood ◽

10.1182/blood.2021012805 ◽

2021 ◽

Author(s):

Miguel A Galindo-Campos ◽

Nura Lutfi ◽

Sarah Bonnin ◽

Carlos Martínez ◽

Talia Velasco-Hernandez ◽

...

Keyword(s):

Dna Damage ◽

B Cells ◽

B Cell ◽

Immune Escape ◽

Cell Lymphoma ◽

Tumour Progression ◽

Cancer Therapeutics ◽

B Cell Lymphoma ◽

B Cell Lymphomas ◽

Parp 1

Dysregulation of the c-Myc oncogene occurs in a wide variety of haematologic malignancies and its overexpression has been linked with aggressive tumour progression. Here, we show that Poly (ADP-ribose) polymerase (PARP)-1 and PARP-2 exert opposing influences on progression of c-Myc-driven B-cell lymphomas. PARP-1 and PARP-2 catalyse the synthesis and transfer of ADP-ribose units onto amino acid residues of acceptor proteins in response to DNA-strand breaks, playing a central role in the response to DNA damage. Accordingly, PARP inhibitors have emerged as promising new cancer therapeutics. However, the inhibitors currently available for clinical use are not able to discriminate between individual PARP proteins. We found that genetic deletion of PARP-2 prevents c-Myc-driven B-cell lymphomas, while PARP-1-deficiency accelerates lymphomagenesis in the Em-Myc mouse model of aggressive B-cell lymphoma. Loss of PARP-2 aggravates replication stress in pre-leukemic Em-Myc B cells resulting in accumulation of DNA damage and concomitant cell death that restricts the c-Myc-driven expansion of B cells, thereby providing protection against B-cell lymphoma. In contrast, PARP-1-deficiency induces a proinflammatory response, and an increase in regulatory T cells likely contributing to immune escape of B-cell lymphomas, resulting in an acceleration of lymphomagenesis. These findings pinpoint specific functions for PARP-1 and PARP-2 in c-Myc-driven lymphomagenesis with antagonistic consequences that may help inform the design of new PARP-centred therapeutic strategies with selective PARP-2 inhibition potentially representing a new therapeutic approach for the treatment of c-Myc-driven tumours.

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Decreased DNA damage by acid and increased repair of acid-damaged DNA in acid-habituatedEscherichia coli

Journal of Applied Bacteriology ◽

10.1111/j.1365-2672.1991.tb02748.x ◽

1991 ◽

Vol 70 (6) ◽

pp. 507-511 ◽

Cited By ~ 38

Author(s):

N. Raja ◽

M. Goodson ◽

D.G. Smith ◽

R.J. Rowbury

Keyword(s):

Dna Damage ◽

Damaged Dna

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PARP-1–dependent recruitment of cold-inducible RNA-binding protein promotes double-strand break repair and genome stability

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1713912115 ◽

2018 ◽

Vol 115 (8) ◽

pp. E1759-E1768 ◽

Cited By ~ 14

Author(s):

Jung-Kuei Chen ◽

Wen-Ling Lin ◽

Zhang Chen ◽

Hung-wen Liu

Keyword(s):

Dna Damage ◽

Genome Stability ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Strand Break ◽

Double Strand Break ◽

Dsb Repair ◽

Active Involvement ◽

Parp 1

Maintenance of genome integrity is critical for both faithful propagation of genetic information and prevention of mutagenesis induced by various DNA damage events. Here we report cold-inducible RNA-binding protein (CIRBP) as a newly identified key regulator in DNA double-strand break (DSB) repair. On DNA damage, CIRBP temporarily accumulates at the damaged regions and is poly(ADP ribosyl)ated by poly(ADP ribose) polymerase-1 (PARP-1). Its dissociation from the sites of damage may depend on its phosphorylation status as mediated by phosphatidylinositol 3-kinase-related kinases. In the absence of CIRBP, cells showed reduced γH2AX, Rad51, and 53BP1 foci formation. Moreover, CIRBP-depleted cells exhibited impaired homologous recombination, impaired nonhomologous end-joining, increased micronuclei formation, and higher sensitivity to gamma irradiation, demonstrating the active involvement of CIRBP in DSB repair. Furthermore, CIRBP depleted cells exhibited defects in DNA damage-induced chromatin association of the MRN complex (Mre11, Rad50, and NBS1) and ATM kinase. CIRBP depletion also reduced phosphorylation of a variety of ATM substrate proteins and thus impaired the DNA damage response. Taken together, these results reveal a previously unrecognized role for CIRBP in DSB repair.

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Gain-of-function of poly(ADP-ribose) polymerase-1 upon cleavage by apoptotic proteases: implications for apoptosis

Journal of Cell Science ◽

10.1242/jcs.114.20.3771 ◽

2001 ◽

Vol 114 (20) ◽

pp. 3771-3778 ◽

Cited By ~ 2

Author(s):

Damien D’Amours ◽

Frédéric R. Sallmann ◽

Vishva M. Dixit ◽

Guy G. Poirier

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Catalytic Activity ◽

Dna Binding ◽

Energy Levels ◽

Mouse Fibroblast ◽

Dominant Negative ◽

Energy Depletion ◽

Parp 1

Poly(ADP-ribosyl)ation is an important mechanism for the maintenance of genomic integrity in response to DNA damage. The enzyme responsible for poly(ADP-ribose) synthesis, poly(ADP-ribose) polymerase 1 (PARP-1), has been implicated in two distinct modes of cell death induced by DNA damage, namely apoptosis and necrosis. During the execution phase of apoptosis, PARP-1 is specifically proteolyzed by caspases to produce an N-terminal DNA-binding domain (DBD) and a C-terminal catalytic fragment. The functional consequence of this proteolytic event is not known. However, it has recently been shown that overactivation of full-length PARP-1 can result in energy depletion and necrosis in dying cells. Here, we investigate the molecular basis for the differential involvement of PARP-1 in these two types of cellular demise. We show that the C-terminal apoptotic fragment of PARP-1 loses its DNA-dependent catalytic activity upon cleavage with caspase 3. However, the N-terminal apoptotic fragment, retains a strong DNA-binding activity and totally inhibits the catalytic activity of uncleaved PARP-1. This dominant-negative behavior was confirmed and extended in cellular extracts where DNA repair was completely inhibited by nanomolar concentrations of the N-terminal fragment. Furthermore, overexpression of the apoptotic DBD in mouse fibroblast inhibits endogenous PARP-1 activity very efficiently in vivo, thereby confirming our biochemical observations. Taken together, these experiments indicate that the apoptotic DBD of PARP-1 acts cooperatively with the proteolytic inactivation of the enzyme to trans-inhibit NAD hydrolysis and to maintain the energy levels of the cell. These results are consistent with a model in which cleavage of PARP-1 promotes apoptosis by preventing DNA repair-induced survival and by blocking energy depletion-induced necrosis.

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