scholarly journals Biological Systems that Control Transcription of DNA Repair and Telomere Maintenance-Associated Genes

10.5772/53905 ◽  
2013 ◽  
Author(s):  
Fumiaki Uchiumi ◽  
Steven Larsen ◽  
Sei-ichi Tanum
Keyword(s):  
Dna Repair ◽  
Biological Systems ◽  
Telomere Maintenance

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.

scholarly journals Recent Advances in Understanding Werner Syndrome

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1779 ◽  
Author(s):  
Raghavendra A. Shamanna ◽  
Deborah L. Croteau ◽  
Jong-Hyuk Lee ◽  
Vilhelm A. Bohr
Keyword(s):  
Dna Repair ◽  
Stem Cell ◽  
Genome Stability ◽  
Werner Syndrome ◽  
Genetic Disorder ◽  
Accelerated Aging ◽  
Nutrient Sensing ◽  
Telomere Maintenance ◽  
Telomere Attrition ◽  
Recent Advances

Aging, the universal phenomenon, affects human health and is the primary risk factor for major disease pathologies. Progeroid diseases, which mimic aging at an accelerated rate, have provided cues in understanding the hallmarks of aging. Mutations in DNA repair genes as well as in telomerase subunits are known to cause progeroid syndromes. Werner syndrome (WS), which is characterized by accelerated aging, is an autosomal-recessive genetic disorder. Hallmarks that define the aging process include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulation of nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. WS recapitulates these hallmarks of aging and shows increased incidence and early onset of specific cancers. Genome integrity and stability ensure the normal functioning of the cell and are mainly guarded by the DNA repair machinery and telomeres. WRN, being a RecQ helicase, protects genome stability by regulating DNA repair pathways and telomeres. Recent advances in WS research have elucidated WRN’s role in DNA repair pathway choice regulation, telomere maintenance, resolution of complex DNA structures, epigenetic regulation, and stem cell maintenance.

scholarly journals Visible Light-Induced Oxidative N-dealkylation of Alkylamines by a Luminescent Osmium(VI) Nitrido Complex

2021 ◽  
Author(s):  
Tai-Chu Lau ◽  
Jing Xiang ◽  
Peng Ming ◽  
PAN Yi ◽  
Li-Juan Luo ◽  
...  
Keyword(s):  
Dna Repair ◽  
Visible Light ◽  
Biological Systems ◽  
Drug Detoxification

N-Dealkylation of amines by metal oxo intermediates (M=O) is related with drug detoxification and DNA repair in biological systems. In this study, we report the first example of N-dealkylation of...

Expression of genes involved in DNA repair and telomere maintenance in the yeast Hansenula polymorpha DL1 under heat stress

2015 ◽  
Vol 462 (1) ◽  
pp. 185-188 ◽  
Author(s):  
A. V. Beletsky ◽  
A. N. Malyavko ◽  
M. V. Sukhanova ◽  
E. S. Mardanova ◽  
M. E. Zvereva ◽  
...  
Keyword(s):  
Dna Repair ◽  
Heat Stress ◽  
Hansenula Polymorpha ◽  
Telomere Maintenance ◽  
Expression Of Genes

scholarly journals The Guardian of the Genome Revisited: p53 Downregulates Genes Required for Telomere Maintenance, DNA Repair, and Centromere Structure

Cancers ◽  
2018 ◽  
Vol 10 (5) ◽  
pp. 135 ◽  
Author(s):  
Eléonore Toufektchan ◽  
Franck Toledo
Keyword(s):  
Dna Repair ◽  
P53 Protein ◽  
Bone Marrow Failure ◽  
Dyskeratosis Congenita ◽  
Telomere Maintenance ◽  
Recent Analysis ◽  
Phenotypic Traits ◽  
Mutant P53 ◽  
Genome Maintenance ◽  
The Guardian

The p53 protein has been extensively studied for its capacity to prevent proliferation of cells with a damaged genome. Surprisingly, however, our recent analysis of mice expressing a hyperactive mutant p53 that lacks the C-terminal domain revealed that increased p53 activity may alter genome maintenance. We showed that p53 downregulates genes essential for telomere metabolism, DNA repair, and centromere structure and that a sustained p53 activity leads to phenotypic traits associated with dyskeratosis congenita and Fanconi anemia. This downregulation is largely conserved in human cells, which suggests that our findings could be relevant to better understand processes involved in bone marrow failure as well as aging and tumor suppression.

scholarly journals Recombination-Based Telomere Maintenance Is Dependent on Tel1-MRN and Rap1 and Inhibited by Telomerase, Taz1, and Ku in Fission Yeast

2007 ◽  
Vol 28 (5) ◽  
pp. 1443-1455 ◽  
Author(s):  
Lakxmi Subramanian ◽  
Bettina A. Moser ◽  
Toru M. Nakamura
Keyword(s):  
Dna Repair ◽  
Fission Yeast ◽  
Catalytic Subunit ◽  
Telomere Maintenance ◽  
Yeast Cells ◽  
Eukaryotic Cells ◽  
Checkpoint Kinase ◽  
Telomere Binding Protein ◽  
Evolutionarily Conserved ◽  
Linear Chromosomes

ABSTRACT Fission yeast cells survive loss of the telomerase catalytic subunit Trt1 (TERT) through recombination-based telomere maintenance or through chromosome circularization. Although trt1Δ survivors with linear chromosomes can be obtained, they often spontaneously circularize their chromosomes. Therefore, it was difficult to establish genetic requirements for telomerase-independent telomere maintenance. In contrast, when the telomere-binding protein Taz1 is also deleted, taz1Δ trt1Δ cells are able to stably maintain telomeres. Thus, taz1Δ trt1Δ cells can serve as a valuable tool in understanding the regulation of telomerase-independent telomere maintenance. In this study, we show that the checkpoint kinase Tel1 (ATM) and the DNA repair complex Rad32-Rad50-Nbs1 (MRN) are required for telomere maintenance in taz1Δ trt1Δ cells. Surprisingly, Rap1 is also essential for telomere maintenance in taz1Δ trt1Δ cells, even though recruitment of Rap1 to telomeres depends on Taz1. Expression of catalytically inactive Trt1 can efficiently inhibit recombination-based telomere maintenance, but the inhibition requires both Est1 and Ku70. While Est1 is essential for recruitment of Trt1 to telomeres, Ku70 is dispensable. Thus, we conclude that Taz1, TERT-Est1, and Ku70-Ku80 prevent telomere recombination, whereas MRN-Tel1 and Rap1 promote recombination-based telomere maintenance. Evolutionarily conserved proteins in higher eukaryotic cells might similarly contribute to telomere recombination.

Emerging roles of SIRT6 on telomere maintenance, DNA repair, metabolism and mammalian aging

2012 ◽  
Vol 364 (1-2) ◽  
pp. 345-350 ◽  
Author(s):  
Gaoxiang Jia ◽  
Ling Su ◽  
Sunil Singhal ◽  
Xiangguo Liu
Keyword(s):  
Dna Repair ◽  
Telomere Maintenance

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.

Sign in / Sign up

Export Citation Format

Share Document