Deficiency in Poly(ADP-ribose) Polymerase-1 (PARP-1) Accelerates Aging and Spontaneous Carcinogenesis in Mice

Genetic and biochemical studies have shown that PARP-1 and poly(ADP-ribosyl)ation play an important role in DNA repair, genomic stability, cell death, inflammation, telomere maintenance, and suppressing tumorigenesis, suggesting that the homeostasis of poly(ADP-ribosyl)ation and PARP-1 may also play an important role in aging. Here we show that PARP- mice exhibit a reduction of life span and a significant increase of population aging rate. Analysis of noninvasive parameters, including body weight gain, body temperature, estrous function, behavior, and a number of biochemical indices suggests the acceleration of biological aging in PARP- mice. The incidence of spontaneous tumors in both PARP- and PARP- groups is similar; however, malignant tumors including uterine tumors, lung adenocarcinomas and hepatocellular carcinomas, develop at a significantly higher frequency in PARP- mice than PARP- mice (72% and 49%, resp.; .05). In addition, spontaneous tumors appear earlier in PARP- mice compared to the wild type group. Histopathological studies revealed a wide spectrum of tumors in uterus, ovaries, liver, lungs, mammary gland, soft tissues, and lymphoid organs in both groups of the mice. These results demonstrate that inactivation of DNA repair gene PARP-1 in mice leads to acceleration of aging, shortened life span, and increased spontaneous carcinogenesis.

Download Full-text

Methylation–unmethylation response of the promoter of DNA repair gene poly(ADP-ribose)polymerases (PARP-1) to inflammatory mediators and anti-inflammatory drugs in human lung

Toxicology Letters ◽

10.1016/j.toxlet.2010.03.619 ◽

2010 ◽

Vol 196 ◽

pp. S182

Author(s):

R. Gherbal ◽

H. Hamed ◽

B. Sacher ◽

A. Torky ◽

H. Foth

Keyword(s):

Dna Repair ◽

Inflammatory Mediators ◽

Human Lung ◽

Repair Gene ◽

Dna Repair Gene ◽

Inflammatory Drugs ◽

Anti Inflammatory ◽

Parp 1

Download Full-text

Female age affects DNA repair gene expression in mouse GV oocytes from stimulated and unstimulated cycles and in MII oocytes matured in-vivo and in-vitro

10.26226/morressier.5af300ae738ab10027aa9430 ◽

2018 ◽

Author(s):

AR AR ◽

Sally Catt

Keyword(s):

Gene Expression ◽

Dna Repair ◽

Repair Gene ◽

Female Age ◽

Dna Repair Gene ◽

Mouse Gv Oocytes

Download Full-text

Faculty Opinions recommendation of Intraductal/ductal histology and lymphovascular invasion are associated with germline DNA-repair gene mutations in prostate cancer.

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

10.3410/f.732569033.793548738 ◽

2018 ◽

Author(s):

Valeri Vasioukhin

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Lymphovascular Invasion ◽

Gene Mutations ◽

Repair Gene ◽

Dna Repair Gene

Download Full-text

Discovery of pyrano[2,3-d]pyrimidine-2,4-dione derivatives as novel PARP-1 inhibitors: design, synthesis and antitumor activity

RSC Advances ◽

10.1039/d0ra10321g ◽

2021 ◽

Vol 11 (8) ◽

pp. 4454-4464

Author(s):

Nour E. A. Abd El-sattar ◽

Eman H. K. Badawy ◽

Eman Z. Elrazaz ◽

Nasser S. M. Ismail

Keyword(s):

Cell Death ◽

Dna Repair ◽

Antitumor Activity ◽

Cancer Cell ◽

Cytotoxic Agents ◽

Repair Mechanism ◽

Design Synthesis ◽

Parp 1

PARP-1 are involved in DNA repair damage and so PARP-1 inhibitors have been used as potentiators in combination with DNA damaging cytotoxic agents to compromise the cancer cell DNA repair mechanism, resulting in genomic dysfunction and cell death.

Download Full-text

DNA Repair Gene Polymorphism and the Risk of Mitral Chordae Tendineae Rupture

Disease Markers ◽

10.1155/2015/825020 ◽

2015 ◽

Vol 2015 ◽

pp. 1-6

Author(s):

Aysel Kalayci Yigin ◽

Mehmet Bulent Vatan ◽

Ramazan Akdemir ◽

Muhammed Necati Murat Aksoy ◽

Mehmet Akif Cakar ◽

...

Keyword(s):

Dna Repair ◽

Fragment Length Polymorphism ◽

Control Group ◽

Chordae Tendineae ◽

Repair Gene ◽

Repair Capacity ◽

Dna Repair Capacity ◽

Dna Repair Gene ◽

Increased Risk ◽

Polymerase Chain

Polymorphisms in Lys939Gln XPC gene may diminish DNA repair capacity, eventually increasing the risk of carcinogenesis. The aim of the present study was to evaluate the significance of polymorphism Lys939Gln in XPC gene in patients with mitral chordae tendinea rupture (MCTR). Twenty-one patients with MCTR and thirty-seven age and sex matched controls were enrolled in the study. Genotyping of XPC gene Lys939Gln polymorphism was carried out using polymerase chain reaction- (PCR-) restriction fragment length polymorphism (RFLP). The frequencies of the heterozygote genotype (Lys/Gln-AC) and homozygote genotype (Gln/Gln-CC) were significantly different in MCTR as compared to control group, respectively (52.4% versus 43.2%,p=0.049; 38.15% versus 16.2%,p=0.018). Homozygote variant (Gln/Gln) genotype was significantly associated with increased risk of MCTR (OR = 2.059; 95% CI: 1.097–3.863;p=0.018). Heterozygote variant (Lys/Gln) genotype was also highly significantly associated with increased risk of MCTR (OR = 1.489; 95% CI: 1.041–2.129;p=0.049). The variant allele C was found to be significantly associated with MCTR (OR = 1.481; 95% CI: 1.101–1.992;p=0.011). This study has demonstrated the association of XPC gene Lys939Gln polymorphism with MCTR, which is significantly associated with increased risk of MCTR.

Download Full-text

DNA Repair Gene Polymorphisms and Susceptibility to Urothelial Carcinoma in a Southeastern European Population

Current Oncology ◽

10.3390/curroncol28030174 ◽

2021 ◽

Vol 28 (3) ◽

pp. 1879-1885

Author(s):

Maria Samara ◽

Maria Papathanassiou ◽

Lampros Mitrakas ◽

George Koukoulis ◽

Panagiotis J. Vlachostergios ◽

...

Keyword(s):

Dna Repair ◽

Urothelial Carcinoma ◽

European Population ◽

Nucleotide Polymorphisms ◽

Environmental Carcinogens ◽

Repair Gene ◽

High Exposure ◽

Dna Repair Gene ◽

Increased Risk ◽

Xrcc3 Thr241met

Single nucleotide polymorphisms (SNPs) in DNA repair genes may predispose to urothelial carcinoma of the bladder (UCB). This study focused on three specific SNPs in a population with high exposure to environmental carcinogens including tobacco and alcohol. A case-control study design was used to assess for presence of XPC PAT +/−, XRCC3 Thr241Met, and ERCC2 Lys751Gln DNA repair gene SNPs in peripheral blood from patients with UCB and healthy individuals. One hundred patients and equal number of healthy subjects were enrolled. The XPC PAT +/+ genotype was associated with a 2-fold increased risk of UCB (OR = 2.16; 95%CI: 1.14–4; p = 0.01). The −/+ and +/+ XPC PAT genotypes were more frequently present in patients with multiple versus single tumors (p = 0.01). No association was detected between ERCC2 Lys751Gln genotypes/alleles, and risk for developing UCB. Presence of the XRCC3 TT genotype (OR = 0.14; 95%CI:0.07–0.25; p < 0.01) and of the T allele overall (OR = 0.26; 95%CI:0.16–0.41; p < 0.01) conferred a protective effect against developing UCB. The XPC PAT −/+ and XRCC3 Thr241Met SNPs are associated with predisposition to UCB. The XPC PAT −/+ SNP is also an indicator of bladder tumor multiplicity, which might require a more individualized surveillance and treatment.

Download Full-text

Patients with Systemic Sclerosis Present Increased DNA Damage Differentially Associated with DNA Repair Gene Polymorphisms

The Journal of Rheumatology ◽

10.3899/jrheum.130376 ◽

2014 ◽

Vol 41 (3) ◽

pp. 458-465 ◽

Cited By ~ 11

Author(s):

Gustavo Martelli Palomino ◽

Carmen L. Bassi ◽

Isabela J. Wastowski ◽

Danilo J. Xavier ◽

Yara M. Lucisano-Valim ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Systemic Sclerosis ◽

Blood Cells ◽

Gene Polymorphisms ◽

Peripheral Blood Cells ◽

Dna Repair Genes ◽

Repair Gene ◽

Dna Repair Gene ◽

Repair Genes

Objective.Patients with systemic sclerosis (SSc) exhibit increased toxicity when exposed to genotoxic agents. In our study, we evaluated DNA damage and polymorphic sites in 2 DNA repair genes (XRCC1Arg399Gln andXRCC4Ile401Thr) in patients with SSc.Methods.A total of 177 patients were studied for DNA repair gene polymorphisms. Fifty-six of them were also evaluated for DNA damage in peripheral blood cells using the comet assay.Results.Compared to controls, the patients as a whole or stratified into major clinical variants (limited or diffuse skin involvement), irrespective of the underlying treatment schedule, exhibited increased DNA damage.XRCC1(rs: 25487) andXRCC4(rs: 28360135) allele and genotype frequencies observed in patients with SSc were not significantly different from those observed in controls; however, theXRCC1Arg399Gln allele was associated with increased DNA damage only in healthy controls and theXRCC4Ile401Thr allele was associated with increased DNA damage in both patients and controls. Further, theXRCC1Arg399Gln allele was associated with the presence of antinuclear antibody and anticentromere antibody. No association was observed between these DNA repair gene polymorphic sites and clinical features of patients with SSc.Conclusion.These results corroborate the presence of genomic instability in SSc peripheral blood cells, as evaluated by increased DNA damage, and show that polymorphic sites of theXRCC1andXRCC4DNA repair genes may differentially influence DNA damage and the development of autoantibodies.

Download Full-text