Distinct kinetics of DNA repair protein accumulation at DNA lesions and cell cycle-dependent formation of γH2AX- and NBS1-positive repair foci

2015 ◽  
Vol 107 (12) ◽  
pp. 440-454 ◽  
Author(s):  
Jana Suchánková ◽  
Stanislav Kozubek ◽  
Soňa Legartová ◽  
Petra Sehnalová ◽  
Thomas Küntziger ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Dna Lesions ◽  
Protein Accumulation ◽  
Repair Protein ◽  
Dna Repair Protein ◽  
Cycle Dependent ◽  
Kinetics Of

scholarly journals Synergistic Inhibitory Effect of Ionizing Radiation Combined With Imatinib on Gastrointestinal Stromal Tumor Cell and Its Mechanism

2020 ◽  
Author(s):  
Wenbiao Xiao ◽  
Yongjian Zhou ◽  
Guosheng Lin ◽  
Renjie Guo
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Radiation Damage ◽  
Molecular Mechanism ◽  
Inhibitory Effect ◽  
Signal Pathway ◽  
High Expression ◽  
Migration And Invasion ◽  
Repair Protein ◽  
Dna Repair Protein

Abstract BackgroundRT is considered insensitive to GIST,However, recently, the effective clinical practice of RT in GIST has been reported,The purpose of this study was to clarify the synergistic effect of RT combined with IM on GIST and the potential molecular mechanism.MethodsThe expression of DNA repair genes related to IR in 100 patients with GIST and their matched tissues was studied by IHC.The relationship between them and clinicopathological characteristics and risk of GIST was analyzed.The effects of IR combined with IM on the proliferation, clonogenesis, invasion and migration, cell cycle and apoptosis of GIST-882 cell were examined by cell count, CCK-8, plate cloning, scratch and transwell, and flow cytometry.Combined with KEGG database signal pathway analysis, qPCR and westernblot were used to study the potential molecular mechanism of coordinated inhibition of IM combined with IR on GIST-882 cell.ResultsThe expression of DNA repair protein related to IR injury in GIST was significantly higher than that in matched adjacent tissues, and the high expression of Rad51 was related to the high risk of GIST (P < 0.05).The interaction between IR and IM was strong by factorial design analysis (P < 0.05). The combined index of choutalalay analysis also proved the above conclusion.Compared with the single effect, the combined effect significantly enhanced the ability of clone formation, migration and invasion, and the inhibition of apoptosis of GIST-882 cells.In cell cycle study,IM mainly leads to direct apoptosis, while IR leads to cell cycle arrest in S and G2 / M phases.In the study of molecular mechanism, it was found that IR damage can feedback stimulate the high expression of DNA repair protein in cells, while im may enhance IR sensitivity by inhibiting the expression of radiation damage related DNA repair protein Rad51 in p53 signaling pathway.ConclusionsIM combined with IR can synergistically inhibit the proliferation, apoptosis, clonogenesis, invasion, migration and cell cycle of GIST cells. The mechanism of synergism may be through IM to inhibit p53, a signal pathway of radiation damage repair.

scholarly journals Biphasic Kinetics of the Human DNA Repair Protein MED1 (MBD4), a Mismatch-specific DNAN-Glycosylase

2000 ◽  
Vol 275 (42) ◽  
pp. 32422-32429 ◽  
Author(s):  
Fiorella Petronzelli ◽  
Antonio Riccio ◽  
George D. Markham ◽  
Steven H. Seeholzer ◽  
Jay Stoerker ◽  
...  
Keyword(s):  
Dna Repair ◽  
Biphasic Kinetics ◽  
Human Dna ◽  
Repair Protein ◽  
Dna Repair Protein ◽  
Kinetics Of

scholarly journals Cell cycle–dependent chromatin loading of the Fanconi anemia core complex by FANCM/FAAP24

Blood ◽  
2008 ◽  
Vol 111 (10) ◽  
pp. 5215-5222 ◽  
Author(s):  
Jung Min Kim ◽  
Younghoon Kee ◽  
Allan Gurtan ◽  
Alan D. D'Andrea
Keyword(s):  
Cell Cycle ◽  
Fanconi Anemia ◽  
Cancer Susceptibility ◽  
Bone Marrow Failure ◽  
Core Complex ◽  
Developmental Abnormalities ◽  
Repair Protein ◽  
Dna Repair Protein ◽  
Human Ortholog ◽  
Cycle Dependent

Abstract Fanconi anemia (FA) is a genetic disease characterized by congenital abnormalities, bone marrow failure, and cancer susceptibility. A total of 13 FA proteins are involved in regulating genome surveillance and chromosomal stability. The FA core complex, consisting of 8 FA proteins (A/B/C/E/F/G/L/M), is essential for the monoubiquitination of FANCD2 and FANCI. FANCM is a human ortholog of the archaeal DNA repair protein Hef, and it contains a DEAH helicase and a nuclease domain. Here, we examined the effect of FANCM expression on the integrity and localization of the FA core complex. FANCM was exclusively localized to chromatin fractions and underwent cell cycle–dependent phosphorylation and dephosphorylation. FANCM-depleted HeLa cells had an intact FA core complex but were defective in chromatin localization of the complex. Moreover, depletion of the FANCM binding partner, FAAP24, disrupted the chromatin association of FANCM and destabilized FANCM, leading to defective recruitment of the FA core complex to chromatin. Our results suggest that FANCM is an anchor required for recruitment of the FA core complex to chromatin, and that the FANCM/FAAP24 interaction is essential for this chromatin-loading activity. Dysregulated loading of the FA core complex accounts, at least in part, for the characteristic cellular and developmental abnormalities in FA.

scholarly journals Human MMS21/NSE2 Is a SUMO Ligase Required for DNA Repair

2005 ◽  
Vol 25 (16) ◽  
pp. 7021-7032 ◽  
Author(s):  
Patrick Ryan Potts ◽  
Hongtao Yu
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Ectopic Expression ◽  
Well Being ◽  
Dna Lesions ◽  
Wild Type ◽  
Sumo Ligase ◽  
Repair Protein ◽  
Dna Repair Protein ◽  
Induced Apoptosis

ABSTRACT DNA repair is required for the genomic stability and well-being of an organism. In yeasts, a multisubunit complex consisting of SMC5, SMC6, MMS21/NSE2, and other non-SMC proteins is required for DNA repair through homologous recombination. The yeast MMS21 protein is a SUMO ligase. Here we show that the human homolog of MMS21 is also a SUMO ligase. hMMS21 stimulates sumoylation of hSMC6 and the DNA repair protein TRAX. Depletion of hMMS21 by RNA interference (RNAi) sensitizes HeLa cells toward DNA damage-induced apoptosis. Ectopic expression of wild-type hMMS21, but not its ligase-inactive mutant, rescues this hypersensitivity of hMMS21-RNAi cells. ATM/ATR are hyperactivated in hMMS21-RNAi cells upon DNA damage. Consistently, hMMS21-RNAi cells show an increased number of phospho-CHK2 foci. Finally, we show that hMMS21-RNAi cells show a decreased capacity to repair DNA lesions as measured by the comet assay. Our findings suggest that the human SMC5/6 complex and the SUMO ligase activity of hMMS21 are required for the prevention of DNA damage-induced apoptosis by facilitating DNA repair in human cells.

scholarly journals The Interactions of DNA Repair, Telomere Homeostasis, and p53 Mutational Status in Solid Cancers: Risk, Prognosis, and Prediction

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 479
Author(s):  
Pavel Vodicka ◽  
Ladislav Andera ◽  
Alena Opattova ◽  
Ludmila Vodickova
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Dna Lesions ◽  
Cell Cycle Checkpoint ◽  
Solid Cancer ◽  
Genomic Integrity ◽  
Repair Capacity ◽  
Mutational Status ◽  
Telomere Homeostasis

The disruption of genomic integrity due to the accumulation of various kinds of DNA damage, deficient DNA repair capacity, and telomere shortening constitute the hallmarks of malignant diseases. DNA damage response (DDR) is a signaling network to process DNA damage with importance for both cancer development and chemotherapy outcome. DDR represents the complex events that detect DNA lesions and activate signaling networks (cell cycle checkpoint induction, DNA repair, and induction of cell death). TP53, the guardian of the genome, governs the cell response, resulting in cell cycle arrest, DNA damage repair, apoptosis, and senescence. The mutational status of TP53 has an impact on DDR, and somatic mutations in this gene represent one of the critical events in human carcinogenesis. Telomere dysfunction in cells that lack p53-mediated surveillance of genomic integrity along with the involvement of DNA repair in telomeric DNA regions leads to genomic instability. While the role of individual players (DDR, telomere homeostasis, and TP53) in human cancers has attracted attention for some time, there is insufficient understanding of the interactions between these pathways. Since solid cancer is a complex and multifactorial disease with considerable inter- and intra-tumor heterogeneity, we mainly dedicated this review to the interactions of DNA repair, telomere homeostasis, and TP53 mutational status, in relation to (a) cancer risk, (b) cancer progression, and (c) cancer therapy.

scholarly journals A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M

2005 ◽  
Vol 37 (9) ◽  
pp. 958-963 ◽  
Author(s):  
Amom Ruhikanta Meetei ◽  
Annette L Medhurst ◽  
Chen Ling ◽  
Yutong Xue ◽  
Thiyam Ramsing Singh ◽  
...  
Keyword(s):  
Dna Repair ◽  
Fanconi Anemia ◽  
Complementation Group ◽  
Repair Protein ◽  
Dna Repair Protein ◽  
Human Ortholog
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