scholarly journals Cells Deficient in the Shwachman-Diamond Syndrome Protein SBDS or the Diamond-Blackfan Anemia Protein RPS19 Have Impaired Homologous Recombination

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 104-104
Author(s):  
Elif Asik ◽  
Nimrat Chatterjee ◽  
Alison A. Bertuch
Keyword(s):  
Dna Repair ◽  
Ribosome Biogenesis ◽  
Telomere Maintenance ◽  
The Other ◽  
Dsb Repair ◽  
Rad51 Protein ◽  
Protein Levels ◽  
Diamond Blackfan Anemia ◽  
Shwachman Diamond Syndrome ◽  
Subunit Joining

The inherited bone marrow failure syndromes (IBMFS) are rare genetic disorders caused by mutations in critical components of fundamental cellular processes such as ribosome biogenesis, DNA repair, and telomere maintenance. The IBMFS Shwachman-Diamond syndrome(SDS) and Diamond-Blackfan anemia (DBA) are classified as ribosomopathies due to etiologic mutations in genes encoding factors involved in ribosome biogenesis (SBDSin the majority of patients with SDS) or ribosomal proteins (RPS19most commonly in patients with DBA). Although these disorders can be distinguished clinically and from the other IBMFS, they share with each other and with other IBMFS increased predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Whereas genomic instability due to defective DNA repair or telomere maintenance is thought to underlie cancer predisposition in the IBMFS Fanconi anemia and dyskeratosis congenita, respectively, the molecular mechanisms driving cancer in SDS and DBA are not fully understood. Our research has focused on DNA repair in SDS and DBA. A prior report suggested lymphoblastoid cell lines (LCLs) derived from patients with SDS arehypersensitive to ionizing radiation (IR). Consistent with this, we found SDS-LCLs had decreased survival following IR compared to control-LCLsin colony survival assays. To determine if this cellular phenotype was unique to SDS or present in the other IBMFS ribosomopathy, DBA, we examined LCLs derived from patients with DBA, including those with mutations in RPS19, RPS26, RPL5and RPL11. We found that the DBA-LCLs were similarly hypersensitive to IR as compared to control-LCLs. Further examination of γ-H2AX, a DNA damage response (DDR) factor and marker of DNA double strand breaks (DSBs), revealed that SDS- and DBA-LCLs had delayed resolution of γ-H2AX foci and increased protein levels at 24 hrs after IR as compared to control LCLs. p53, phospho-ATM, and DNA-PKcs protein levels were also higher in SDS-LCL compared to controls. The decreased survival and increased and sustained DDR following IR led us to hypothesize that SDS and DBA cells have a defect in DSB repair. There are two major pathways of DSB repair in mammals, nonhomologous end-joining (NHEJ) and homology-directed repair (HDR), and loss of either results in hypersensitivity to IR. To examine each pathway, we employed U2OS (human osteosarcoma) and HCT116 (human colon cancer) cells containing an integrated green fluorescent protein HDR or NHEJ reporter transgene. Interestingly, we found that knockdown of either SBDS or RPS19 proteins resulted in an approximately 50% reduction in HDR efficiency but no change in NHEJefficiency compared to the scrambled control in both cell lines. We next sought to determine the mechanism underlying the effect of SBDS and RPS19 deficiency on HDR. A survey of proteins required for HDR revealed a reduction in the recombinase RAD51 in SDS-LCLs and in SBDS-depleted HCT116 and U2OS cells, whereas, an initial survey in SDS-LCLs[e1] of factors involved in NHEJ did not reveal a specific NHEJ factor deficiency. Knockdown of eiF6 is known to rescue the defect in 40S and 60S ribosome subunit joining that manifests in SDS patient cells. However, we found eIF6 depletion failed to rescue the level of RAD51 protein and had no impact on HDR in SBDS-deficient cells. We conclude that decreased RAD51 levels in SBDS-deficient cells might contribute to impaired HDR, however, this decrease is independent of the ribosome subunit joining defect. Similarly, RPS19 knock down resulted in a reduction in RAD51 protein level, suggesting a potentially common pathway. We also asked whether SBDS or RPS19 might be more directly involved in the DDR or repair of DSBs. Consistent with this, we found SBDS and RPS19 recruited to chromatin surrounding an I-Sce1 site following DSB induction in chromatin immunoprecipitation assays. Collectively, these findings provide evidence that SBDS and RPS19 may be directly involved in the DDR or DSB repair and raise the possibility that loss of this function may contribute to MDS/AML predisposition in SDS and DBA patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Homologous recombination defects in Shwachman-Diamond syndrome and Diamond-Blackfan anemia

2020 ◽  
Author(s):  
Elif Asik ◽  
Nimrat Chatterjee ◽  
Alison A. Bertuch
Keyword(s):  
Homologous Recombination ◽  
Ribosome Biogenesis ◽  
Strand Break ◽  
Cancer Predisposition ◽  
Parp Inhibition ◽  
Dsb Repair ◽  
Diamond Blackfan Anemia ◽  
Dna Double Strand Break ◽  
Damage Response ◽  
Shwachman Diamond Syndrome

ABSTRACTShwachman-Diamond syndrome (SDS) and Diamond-Blackfan anemia (DBA) are ribosomopathies characterized by impaired hematopoiesis and cancer predisposition. The mechanisms underlying cancer predisposition in these disorders are not well understood. We found that LCLs derived from patients with SDS or DBA had a prolonged DNA damage response and hypersensitivity to ionizing radiation, suggesting impaired DNA double strand break (DSB) repair. Consistent with this, depletion of SBDS and RPS19, the most common etiologic factors in SDS and DBA, respectively, resulted in reduced homologous recombination (HR) in HCT116 and U2OS cells. Surprisingly, depletion of EFL1, which functions with SBDS in ribosome biogenesis, did not impair HR and depletion of eIF6, which restores ribosome joining in SBDS-depleted cells, did not rescue the HR defect associated with SBDS depletion. Instead, we found SBDS and RPS19 recruitment to sites of DSBs suggesting that SBDS and RPS19 have more proximate roles in regulating HR, independent of their ribosomal functions. We propose that reduced HR shifts DSB repair toward error-prone NHEJ and this may contribute to oncogenesis in SDS and DBA. Additionally, we found SBDS and RPS19 depleted cells were hypersensitive to PARP inhibition, potentially uncovering a therapeutic target for SDS- and DBA-associated malignancies.

A Novel Radiosensitivity Phenotype in Shwachman-Diamond Syndrome Is Mediated By ER Stress Response

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3618-3618
Author(s):  
Nimrat Chatterjee ◽  
Christopher Lee Williams ◽  
Saleh Bhar ◽  
Alison A Bertuch
Keyword(s):  
Bone Marrow ◽  
Dna Repair ◽  
Stress Response ◽  
Er Stress ◽  
Ribosome Biogenesis ◽  
Bone Marrow Failure ◽  
Hek293 Cells ◽  
80S Ribosome ◽  
Er Stress Response ◽  
Shwachman Diamond Syndrome

Abstract Shwachman-Diamond syndrome (SDS), an autosomal recessive disorder, is characterized by bone marrow dysfunction, exocrine pancreatic insufficiency, congenital abnormalities, and leukemia predisposition (Myers et al., 2012). Most patients with SDS harbor biallelic mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. SBDS is known to play a role in ribosome biogenesis by enabling eviction of the ribosome anti-association factor eIF6 from the 60S ribosomal subunit, to allow formation of the 80S ribosome (Wong et al., 2011). SBDS-depleted cells are, therefore, defective in ribosome assembly. In addition, absence of SBDS sensitizes cells to ultraviolet irradiation, translation inhibitors, and endoplasmic reticulum (ER) stressors, such as tunicamycin (Ball et al., 2009). A recent report indicated that lymphoblastoid cell lines (LCLs) derived from two SDS patients accumulated more DNA damage after being exposed to ionizing radiation (IR) (Morini et al., 2015). A deficiency in DNA repair was alluded to as a possible cause, however, the mechanism underlying this previously unreported phenotype was not determined. In this study, we investigated LCLs derived from five SDS patients with biallelic SBDS mutations and found all to be hypersensitive to IR in a colony survival assay. In this assay, increasing doses of IR resulted in a significantly lower survival fraction in SDS-compared to control-LCLs. We found SBDS expression to increase in control-cells when stressed with IR, suggesting that SBDS is a stress response protein and its absence in SDS-LCLs induces hypersensitivity to IR. Because knockdown of SBDS in HEK293 cells induces an ER stress response (Ball et al., 2009), we examined the expression of the ER stress response factor phospho-eIF2α in untreated and IR exposed SDS-LCLs and found phospho-eIF2α expression to be markedly increased compared to controls. This result indicated that SDS-LCLs may have an activated ER stress response, as was further confirmed by exposing these cells to additional ER stressors, tunicamycin and H2O2, and observing a similar upregulation of phospho-eIF2α. Because ER stress is known to suppress DNA double strand break (DSBR) (Yamamori et al., 2013), we examined the expression of Rad51 and Ku70, which are required for the homology-directed and nonhomologous end-joining pathways of DSBR, respectively. Surprisingly, we found Rad51 and Ku70 protein levels to be repressed in SDS-LCLs compared to controls, both with and without exposure to IR. Collectively, these data support the hypothesis that, in addition to its role in ribosome biogenesis, SBDS is a stress response protein that plays an important role in regulating the ER stress response. In SDS-cells, where SBDS is lacking, activated ER stress represses DNA repair proteins rendering cells hypersensitive to IR and other stresses. This novel pathway to ER stress induction may contribute to the bone marrow failure and cancer predisposition seen in SDS patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Enhanced p53 Levels Are Involved in the Reduced Mineralization Capacity of Osteoblasts Derived from Shwachman–Diamond Syndrome Subjects

2021 ◽  
Vol 22 (24) ◽  
pp. 13331
Author(s):  
Annalisa Frattini ◽  
Simona Bolamperti ◽  
Roberto Valli ◽  
Marco Cipolli ◽  
Rita Maria Pinto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alkaline Phosphatase ◽  
Ribosome Biogenesis ◽  
Collagen Type ◽  
Bone Marrow Failure ◽  
Pancreatic Insufficiency ◽  
Collagen Type I ◽  
Type I ◽  
Protein Levels ◽  
Shwachman Diamond Syndrome

Shwachman–Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by bone marrow failure, exocrine pancreatic insufficiency, and skeletal abnormalities, caused by loss-of-function mutations in the SBDS gene, a factor involved in ribosome biogenesis. By analyzing osteoblasts from SDS patients (SDS-OBs), we show that SDS-OBs displayed reduced SBDS gene expression and reduced/undetectable SBDS protein compared to osteoblasts from healthy subjects (H-OBs). SDS-OBs cultured in an osteogenic medium displayed a lower mineralization capacity compared to H-OBs. Whole transcriptome analysis showed significant differences in the gene expression of SDS-OBs vs. H-OBs, particularly in the ossification pathway. SDS-OBs expressed lower levels of the main genes responsible for osteoblastogenesis. Of all downregulated genes, Western blot analyses confirmed lower levels of alkaline phosphatase and collagen type I in SDS-OBs than in H-OBs. Interestingly, SDS-OBs showed higher protein levels of p53, an inhibitor of osteogenesis, compared to H-OBs. Silencing of Tp53 was associated with higher collagen type I and alkaline phosphatase protein levels and an increase in SDS-OB mineralization capacity. In conclusion, our results show that the reduced capacity of SDS-OBs to mineralize is mediated, at least in part, by the high levels of p53 and highlight an important role of SBDS in osteoblast functions.

SBDS and eIF6 Modulate Ribosome Subunit Joining in Shwachman Diamond Syndrome,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3438-3438
Author(s):  
Nicholas Burwick ◽  
Scott Coats ◽  
Akiko Shimamura
Keyword(s):  
Stromal Cells ◽  
Ribosome Biogenesis ◽  
Conflicts Of Interest ◽  
Ribosomal Subunit ◽  
Marrow Stromal Cells ◽  
Vitro Assay ◽  
Amino Terminal ◽  
Shwachman Diamond Syndrome ◽  
Subunit Joining

Abstract Abstract 3438 Shwachman Diamond syndrome (SDS) is an autosomal recessive marrow failure syndrome with a predisposition to leukemia. Over 90% of SDS patients harbor biallelic mutations in the SBDS gene. SBDS has been implicated in several cellular functions including ribosome biogenesis and mitotic spindle stabilization. Deletion of SBDS orthologues in yeast results in a severe slow growth phenotype and depressed polysomes. Homozygous deletion of Sbds in murine models results in early embryonic lethality, while conditional deletion of Sbds in mouse liver demonstrates accumulation of 40S and 60S subunits and halfmer formation consistent with impaired ribosome joining. SBDS facilitates the release of eIF6, a factor that prevents ribosome joining. The dramatic phenotypic and polysome changes noted in these experimental models were not observed in cells derived from SDS patients. SDS patient cells have only a mildly reduced growth rate compared to heatlhy controls, and polysome profiles do not demonstrate depressed polysomes or halfmer formation. Since complete abrogation of SBDS expression is lethal and biallelic null mutations in SBDS have not been reported, we examined the role of SBDS and eIF6 in SDS patients and human cell models. We first investigated whether ribosome subunit homeostasis is impaired in SDS patient cells. We find that the 60S:40S ribosomal subunit ratio is consistently reduced in bone marrow stromal cells from SDS patients of different genotypes (n=4). This impairment in 60S:40S ratio is demonstrated in both SDS patient stromal cells and patient lymphoblasts. Stable lentiviral knockdown of SDS in normal marrow stromal cells recapitulates the reduction in 60S:40S ratio. SBDS and eIF6 co-sediment in polysome gradients of human SDS cells. This co-sedimentation is specific for the 60S ribosomal subunit. Since eIF6 has a role as an anti-joining factor, we next developed an in vitro assay to test for ribosome subunit joining in human cells. In this assay, we validate that over-expression of eIF6 results in reduced ribosome joining, and eIF6 knockdown promotes ribosome joining. Moreover, we find that SDS patient stromal cells and patient lymphoblasts both demonstrate impaired ribosome subunit joining, compared with healthy controls. Importantly, the addition of wild type SBDS or depletion of eIF6 improve ribosome joining in SDS patient cells. We demonstrate that the amino terminal sequences of SBDS are necessary but not sufficient for the association of SBDS with the 60S ribosomal subunit. Insertion of a patient-derived N-terminal SBDS point mutation also results in decreased association of SBDS with the 60S ribosomal subunit. These structure-function studies may help to inform genotype:phenotype correlations in SDS. The role of defective ribosome joining in promoting the SDS hematopoietic phenotype is of particular interest. Ongoing studies are interrogating the role of eIF6 modulation on the hematopoietic phenotype in SBDS- depleted cells. Insights garnered from these experiments will help inform the development of novel agents to improve the hematopoetic defect in human SDS. Disclosures: No relevant conflicts of interest to declare.

Effect of microRNA-124 on homologous recombination protein RAD51 and glioblastoma cells undergoing radiation.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13515-e13515
Author(s):  
Henning S Schäfer ◽  
Reuven Agami ◽  
Gijs van Haaften
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Ionizing Radiation ◽  
Cell Survival ◽  
Cell Line ◽  
Glioblastoma Cell Line ◽  
Glioblastoma Cell ◽  
Reporter Cell ◽  
Dsb Repair ◽  
Rad51 Protein

e13515 Background: The DNA damage repair (DDR) pathways are an essential cell survival mechanism to preserve genomic integrity. In tumor cells, DDR pathways have a huge impact in cell survival, response to therapy and thus prognosis. Our objective is to investigate whether microRNAs (miRs) can influence specific DNA repair pathways. For our studies we focussed on double-strand break (DSB) repair by homologous - (HR) or non-homologous recombination (NHEJ). DSBs are the main lethal lesions induced by ionizing radiation. Methods: A retroviral miR expression library of ~500 miRs was transduced into a HR reporter cell line. For less abundant miRs found in this analysis in silico analysis was performed to detect potential targets. Regulation of HR protein RAD51 by miR-124 could be shown by luciferase assays and immunoblotting. Overexpression of miR-124 in glioblastoma cell line U87 was done by lentiviral constructs. Effect of miR-124 overexpression was revealed by colony – and competetive growth assays. Results: In an unbiased screen we found that miR-124 is less abundantly expressed in a reporter cell population sufficient for HR, suggesting a negative role for these miRs in DSB repair via HR. Reporter assays revealed a negative regulation of RAD51, a key protein of HR pathway, by miR-124. This regulation was specific to a conserved binding motif at the 3` UTR of RAD51. This regulation could also be detected in vivo whereas overexpression of miR-124 leads to downregulation of RAD51 protein levels. Functional experiments in glioblastoma cell line (U87), that express hardly no miR-124, revealed increased sensitivity to ionizing radiation if miR-124 is (re)-expressed. Conclusions: In this work we uncover miRs influencing the cellular DNA-repair machinery. We show that miR-124 influences the repair of DSBs by HR. This effect is specific and mediated by the regulation of RAD51 protein level, an essential component of the HR pathway. Re-expression of miR-124 sensitizes glioblastoma cell line (U87) to radiation in functional experiments. We propose that (re)-expressing miR-124 in glioblastomas could be a new treatment strategy to sensitize this tumors to radiation therapy.

scholarly journals Marrow failure: a window into ribosome biology

Blood ◽  
2014 ◽  
Vol 124 (18) ◽  
pp. 2784-2792 ◽  
Author(s):  
Davide Ruggero ◽  
Akiko Shimamura
Keyword(s):  
Developmental Biology ◽  
Human Disease ◽  
Ribosome Biogenesis ◽  
Current Knowledge ◽  
Protein Biosynthesis ◽  
Dyskeratosis Congenita ◽  
Diamond Blackfan Anemia ◽  
Molecular Studies ◽  
Shwachman Diamond Syndrome ◽  
Medical Importance

Abstract Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and dyskeratosis congenita are inherited syndromes characterized by marrow failure, congenital anomalies, and cancer predisposition. Genetic and molecular studies have uncovered distinct abnormalities in ribosome biogenesis underlying each of these 3 disorders. How defects in ribosomes, the essential organelles required for protein biosynthesis in all cells, cause tissue-specific abnormalities in human disease remains a question of fundamental scientific and medical importance. Here we review the overlapping and distinct clinical features of these 3 syndromes and discuss current knowledge regarding the ribosomal pathways disrupted in each of these disorders. We also explore the increasing complexity of ribosome biology and how this informs our understanding of developmental biology and human disease.

scholarly journals Defective ribosome assembly in Shwachman-Diamond syndrome

Blood ◽  
2011 ◽  
Vol 118 (16) ◽  
pp. 4305-4312 ◽  
Author(s):  
Chi C. Wong ◽  
David Traynor ◽  
Nicolas Basse ◽  
Robert R. Kay ◽  
Alan J. Warren
Keyword(s):  
Ribosome Biogenesis ◽  
Bone Marrow Failure ◽  
Pancreatic Insufficiency ◽  
Ribosomal Subunit ◽  
Initiation Factor ◽  
Ribosome Assembly ◽  
Restrictive Temperature ◽  
Poor Growth ◽  
Shwachman Diamond Syndrome ◽  
Subunit Joining

AbstractShwachman-Diamond syndrome (SDS), a recessive leukemia predisposition disorder characterized by bone marrow failure, exocrine pancreatic insufficiency, skeletal abnormalities and poor growth, is caused by mutations in the highly conserved SBDS gene. Here, we test the hypothesis that defective ribosome biogenesis underlies the pathogenesis of SDS. We create conditional mutants in the essential SBDS ortholog of the ancient eukaryote Dictyostelium discoideum using temperature-sensitive, self-splicing inteins, showing that mutant cells fail to grow at the restrictive temperature because ribosomal subunit joining is markedly impaired. Remarkably, wild type human SBDS complements the growth and ribosome assembly defects in mutant Dictyostelium cells, but disease-associated human SBDS variants are defective. SBDS directly interacts with the GTPase elongation factor-like 1 (EFL1) on nascent 60S subunits in vivo and together they catalyze eviction of the ribosome antiassociation factor eukaryotic initiation factor 6 (eIF6), a prerequisite for the translational activation of ribosomes. Importantly, lymphoblasts from SDS patients harbor a striking defect in ribosomal subunit joining whose magnitude is inversely proportional to the level of SBDS protein. These findings in Dictyostelium and SDS patient cells provide compelling support for the hypothesis that SDS is a ribosomopathy caused by corruption of an essential cytoplasmic step in 60S subunit maturation.

Regulation And Effect Of Telomerase And Telomeric Length In Stem Cells

2020 ◽  
Vol 15 ◽  
Author(s):  
Basak Celtikci ◽  
Gulnihal Kulaksiz Erkmen ◽  
Zeliha Gunnur Dikmen
Keyword(s):  
Telomere Length ◽  
Somatic Cells ◽  
Telomere Maintenance ◽  
The Other ◽  
Telomerase Reverse Transcriptase ◽  
Human Telomerase Reverse Transcriptase ◽  
Telomere Shortening ◽  
Maintenance Mechanism ◽  
Associated Diseases ◽  
Human Telomerase

: Telomeres are the protective end caps of eukaryotic chromosomes and they decide the proliferative lifespan of somatic cells, as the guardians of the cell replication. Telomere length in leucocytes reflects telomere length in other somatic cells. Leucocyte telomere length can be a biomarker of human ageing. The risk of diseases, which are associated with reduced cell proliferation and tissue degeneration, including aging or aging-associated diseases, such as dyskeratosis congenita, cardiovascular diseases, pulmonary fibrosis and aplastic anemia, are correlated with an increase in short telomeres. On the other hand, the risk of diseases, which are associated with increased proliferative growth, including major cancers, is correlated with long telomeres. In most of the cancers, a telomere maintenance mechanism during DNA replication is essential. The reactivation of the functional ribonucleoprotein holoenzyme complex [telomerase] starts the cascade from normal and premalignant somatic cells to advanced malignant cells. Telomerase is overexpressed during the development of cancer and embryonic stem cells, through controlling genome integrity, cancer formation and stemness. Cancer cells have mechanisms to maintain telomeres to avoid initiation of cellular senescence or apoptosis, and halting cell division by critically short telomeres. Modulation of the human telomerase reverse transcriptase is the ratelimiting step for the production of functional telomerase and the telomere maintenance. Human telomerase reverse transcriptase promoter promotes its gene expression only in tumor cells, but not in normal cells. Some cancers activate an alternative lengthening of telomeres maintenance mechanism via DNA recombination to unshorten their telomeres. Not only heritability but also oxidative stress, inflammation, environmental factors, and therapeutic interventions have an effect on telomere shortening, explaining the variability in telomere length across individuals. There have been a large number of publications, which correlate human diseases with progressive telomere shortening. Telomere length of an individual at birth is also important to follow up telomere shortening, and it can be used as biomarkers for healthy aging. On the other hand, understanding of cellular stress factors, which affect stem cell behavior, will be useful in regeneration or treatment in cancer and age-associated diseases. In this review, we will understand the connection between stem cell and telomere biology, cancer, and aging-associated diseases. This connection may be useful for discovering novel drug targets and improve outcomes for patients having cancer and aging-associated diseases.

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

2008 ◽  
Vol 2008 ◽  
pp. 1-11 ◽  
Author(s):  
Tatiana S. Piskunova ◽  
Maria N. Yurova ◽  
Anton I. Ovsyannikov ◽  
Anna V. Semenchenko ◽  
Mark A. Zabezhinski ◽  
...  
Keyword(s):  
Dna Repair ◽  
Life Span ◽  
Soft Tissues ◽  
Telomere Maintenance ◽  
Biological Aging ◽  
Spontaneous Tumors ◽  
Uterine Tumors ◽  
Dna Repair Gene ◽  
Spontaneous Carcinogenesis ◽  
Parp 1

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.

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