DNA repair mechanisms in dividing and non-dividing cells

Iyama, Teruaki; Wilson, David M.

doi:10.1016/j.dnarep.2013.04.015

Cited by 626 publications

(591 citation statements)

References 263 publications

(271 reference statements)

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“…Using this cutoff value, a total of 433 siRNAs were identified that potentially sensitize SW1575 to radiation (Supplementary Table S1). Interestingly, several genes involved in the DNA damage response were amongst these hits, such as RAD51, TOPBP1, HTATIP, RNF168, PNKP, and TRIM28 (15)(16)(17)(18)(19). A more detailed pathway analysis of the hits using Ingenuity Pathway Analysis software (www.ingenuity.com) showed that proteins belonging to specific cellular functions, such as cell-cycle control as well as cell death and survival, were significantly overrepresented in the hit list ( Table 1).…”

Section: Resultsmentioning

confidence: 99%

Genome-wide siRNA Screen Identifies the Radiosensitizing Effect of Downregulation of MASTL and FOXM1 in NSCLC

Nagel

Walsum

Buijze

et al. 2015

Molecular Cancer Therapeutics

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Lung cancer is the most common cancer worldwide and on top of that has a very poor prognosis, which is reflected by a 5-year survival rate of 5% to 15%. Radiotherapy is an integral part of most treatment regimens for this type of tumor, often combined with radiosensitizing cytotoxic drugs. In this study, we identified many genes that could potentially be exploited for targeted radiosensitization using a genome-wide siRNA screen in non-small cell lung cancer (NSCLC) cells. The screen identified 433 siRNAs that potentially sensitize lung cancer cells to radiation. Validation experiments showed that knockdown of expression of Forkhead box M1 (FOXM1) or microtubuleassociated serine/threonine kinase-like (MASTL) indeed causes radiosensitization in a panel of NSCLC cells. Strikingly, this effect was not observed in primary human fibroblasts, suggesting that the observed radiosensitization is specific for cancer cells. Phosphoproteomics analyses with and without irradiation showed that a number of cell-cycle-related proteins were significantly less phosphorylated after MASTL knockdown in comparison to the control, while there were no changes in the levels of phosphorylation of DNA damage response proteins. Subsequent analyses showed that MASTL knockdown cells respond differently to radiation, with a significantly shortened G 2 -M phase arrest and defects in cytokinesis, which are followed by a cell-cycle arrest. In summary, we have identified many potential therapeutic targets that could be used for radiosensitization of NSCLC cells, with MASTL being a very promising and druggable target to combine with radiotherapy.

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Section: Resultsmentioning

confidence: 99%

Genome-wide siRNA Screen Identifies the Radiosensitizing Effect of Downregulation of MASTL and FOXM1 in NSCLC

Nagel

Walsum

Buijze

et al. 2015

Molecular Cancer Therapeutics

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“…O‐6‐methylguanine‐DNA methyltransferase (MGMT) is an enzyme involved in the direct reversal of DNA damage in vitro and postmitotic cells in vivo by methylating agents used clinically for chemotherapy (Iyama & Wilson, 2013; Jiang et al ., 2014). It have been suggested that MGMT may play a role in regulating mouse lifespan (Meira et al ., 2014), but it is not known whether long‐lived mice, such as Snell, GHRKO, and PAPPA‐KO, have altered expression of MGMT.…”

Section: Introductionmentioning

confidence: 99%

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

Dominick

Bowman

et al. 2016

Aging Cell

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SummaryStudies of the mTOR pathway have prompted speculation that diminished mTOR complex‐1 (mTORC1) function may be involved in controlling the aging process. Our previous studies have shown diminished mTORC1 activity in tissues of three long‐lived mutant mice: Snell dwarf mice, growth hormone receptor gene disrupted mice (GHRKO), and in this article, mice deficient in the pregnancy‐associated protein‐A (PAPPA‐KO). The ways in which lower mTOR signals slow aging and age‐related diseases are, however, not well characterized. Here, we show that Snell, GHKRO, and PAPPA‐KO mice express high levels of two proteins involved in DNA repair, O‐6‐methylguanine‐DNA methyltransferase (MGMT) and N‐myc downstream‐regulated gene 1 (NDRG1). Furthermore, we report that lowering mTOR enhances MGMT and NDRG1 protein expression via post‐transcriptional mechanisms. We show that the CCR4‐NOT complex, a post‐transcriptional regulator of gene expression, is downstream of the mTORC1 pathway and may be responsible for the upregulation of MGMT and NDRG1 in all three varieties of long‐lived mice. Our data thus suggest a novel link between DNA repair and mTOR signaling via post‐transcriptional regulation involving specific alteration in the CCR4‐NOT complex, whose modulation could control multiple aspects of the aging process.

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“…Yanlış baz çifti MMR (Mismatch Baz Kesip-Çıkarma Nükleotid Kesip Çıkarma Homolog Rekombinasyon Homolog Olmayan Uç Birleştirme repair) sistemi ile de tamir edilemezse yanlış eşleşmiş bazlar replikasyon sonunda hücrede çift zincir DNA kırıklarının oluşmasına, apoptoz yolağının tetiklenmesine, ayrıca kromozomal anomalilere ve kansere yol açabilir 2,13,15 . Metilasyon ajanlarının hücre DNA'sında oluşturduğu O6-MeG eklentisi, MGMT (O6-metilguanin-DNA-metiltransferaz) isimli bir enzim tarafından tamir edilir ve metilasyon kaldırılır 2,13,16 . MGMT memeli hücre ve dokularında DNA alkilasyon ajanlarının zararlı etkilerine karşı koruyucu bir rol oynamaktadır 11,15 .…”

Section: O6-mgmt Ile Onarımunclassified

“…Endojen faktörler; DNA'da kendiliğinden meydana gelen hatalar olabildiği gibi hücresel metabolizmanın yan ürünü olarak üretilen reaktif oksijen ve nitrojen türleri, lipid peroksidasyon ürünleri, endojen alkilasyon ajanları, östrojen ve kolesterol metabolitleri ve reaktif karbonil türleri de olabilmektedir 1, 2,3 . Ekzojen faktörler ise ultraviole ışığı, iyonize radyasyon, ağır metaller, hava kirliliği, sigara dumanı, kemoterapötik ilaçlar olarak sayılabilmektedir 1, 2,4,5 . Bir memeli genomunda her gün yaklaşık olarak 10 4 'ten daha fazla DNA hasarının ortaya çıktığı tahmin edilmektedir 2,6 .…”

Section: Introductionunclassified

“…Ekzojen faktörler ise ultraviole ışığı, iyonize radyasyon, ağır metaller, hava kirliliği, sigara dumanı, kemoterapötik ilaçlar olarak sayılabilmektedir 1, 2,4,5 . Bir memeli genomunda her gün yaklaşık olarak 10 4 'ten daha fazla DNA hasarının ortaya çıktığı tahmin edilmektedir 2,6 . DNA'daki hasarlar; tek baz değişimi (deaminasyon, depürinasyon, baz alkilasyonu, delesyon, insersiyon vs), tek veya çift zincir kırıkları, aynı veya farklı DNA zincirleri arasında çapraz bağlanma gibi çeşitli şekillerde olabilmektedir 4,7 .…”

Section: Introductionunclassified

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DNA Repair Mechanisms

Kurtoğlu¹,

Tekedereli²

2015

BSBD

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ÖZETİnsan genomik DNA'sının bütünlüğü, endojen ve ekzojen faktörlerin etkisiyle sürekli olarak tehdit altındadır. Bir memeli genomunda her gün yaklaşık olarak 104'ten daha fazla DNA hasarının ortaya çıktığı tahmin edilmektedir. Hasarın yoğunluğuna ve tipine bağlı olarak; hücre döngüsünün durdurulması, gen ifadesinin değişmesi, DNA tamirinin uyarılması, programlı hücre ölümü, kanser ya da yaşlanma gibi olaylar meydana gelebilmektedir. Hücreler genomik bütünlüğü korumak amacıyla karmaşık bir dizi DNA onarım mekanizmalarına sahiplerdir. Bu derlemede, DNA onarım mekanizmaları tartışılmıştır.Anahtar Kelimeler: DNA hasarı, Mutasyon, DNA onarım mekanizmaları SUMMARYThe integrity of human genomic DNA are constantly threatened by the action of endogenous and exogenous factors. It is estimated that more than 104 DNA lesions are occur in each mammalian cell each day. Depending on the intensity and type of the damage; cell cycle arrest, change in gene expression, stimulation of DNA repair, programmed cell death, cancer or cellular aging events may occur. To protect genomic integrity, cells have a complex network of DNA repair mechanisms. In this review, DNA repair mechanisms are discussed in general.

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DNA repair mechanisms in dividing and non-dividing cells

Cited by 626 publications

References 263 publications

Genome-wide siRNA Screen Identifies the Radiosensitizing Effect of Downregulation of MASTL and FOXM1 in NSCLC

Genome-wide siRNA Screen Identifies the Radiosensitizing Effect of Downregulation of MASTL and FOXM1 in NSCLC

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

DNA Repair Mechanisms

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