DNA DSB repair pathway choice: an orchestrated handover mechanism

Kakarougkas, Andreas; Jeggo, Penny A.

doi:10.1259/bjr.20130685

Cited by 237 publications

(197 citation statements)

References 61 publications

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“…The cell cycle phase is the major determinant of the used mechanism. The more effective and less error-prone HR is active only in G2/S phase when the homologous DNA strand can be used as a template [13] while NHEJ operates in all cell cycle phases [14]. In this study, DNA damage was induced with four different DNA DSB-producing mechanisms.…”

Section: Discussionmentioning

confidence: 95%

Extracellular ATP protects endothelial cells against DNA damage

Aho

Helenius

Vattulainen-Collanus

et al. 2016

Purinergic Signalling

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Cell damage can lead to rapid release of ATP to extracellular space resulting in dramatic change in local ATP concentration. Evolutionary, this has been considered as a danger signal leading to adaptive responses in adjacent cells.Our aim was to demonstrate that elevated extracellular ATP or inhibition of ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1/CD39) activity could be used to increase tolerance against DNA-damaging conditions. Human endothelial cells, with increased extracellular ATP concentration in cell proximity, were more resistant to irradiation or chemically induced DNA damage evaluated with the DNA damage markers γH2AX and phosphorylated p53. In our rat models of DNA damage, inhibiting CD39-driven ATP hydrolysis with POM-1 protected the heart and lung tissues against chemically induced DNA damage. Interestingly, the phenomenon could not be replicated in cancer cells. Our results show that transient increase in extracellular ATP can promote resistance to DNA damage.

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Section: Discussionmentioning

confidence: 95%

Extracellular ATP protects endothelial cells against DNA damage

Aho

Helenius

Vattulainen-Collanus

et al. 2016

Purinergic Signalling

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“…The first is homologous recombination (HR), in which free DNA ends are exonucleolytically resected and a complementary sister chromatid is used as a template for synthesis across the break point prior to end rejoining (Kowalczykowski 2015). The dependence on a sister chromatid as a template means that HR is accomplished exclusively in late-S and G2/M phase but is highly accurate, rarely resulting in mutations (Kakarougkas and Jeggo 2014). The second method, nonhomologous end joining (NHEJ), involves direct juxtaposition and relegation of free DNA ends, providing a more efficient, but more error-prone, process (Ochi et al 2014).…”

Section: Npm1 and Ncl In Histone Remodeling And Double Strand Break Rmentioning

confidence: 99%

Nucleolin and nucleophosmin: nucleolar proteins with multiple functions in DNA repair

Scott

Oeffinger

2016

Biochem. Cell Biol.

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The nucleolus represents a highly multifunctional intranuclear organelle in which, in addition to the canonical ribosome assembly, numerous processes such as transcription, DNA repair and replication, the cell cycle and apoptosis are coordinated. The nucleolus is further a key hub in the sensing of cellular stress and undergoes major structural and compositional changes in response to cellular perturbations.Numerous nucleolar proteins have been identified that, upon nucleolar stress sensing, deploy additional, non-ribosomal roles in the regulation of varied cell processes including cell cycle arrest, arrest of DNA replication, induction of DNA repair, and apoptosis, among others. The highly abundant proteins nucleophosmin (NPM1) and nucleolin (NCL) are two such factors that transit to the nucleoplasm in response to stress, and participate directly in the repair of numerous different DNA damages. This review discusses the contributions made by NCL and/or NPM1 to the different DNA repair pathways employed by mammalian cells to repair DNA insults, and examines the implications of such activities for the regulation, pathogenesis and therapeutic targeting of NPM1 and NCL.

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“…The resultant DNA-PK complex activates DNA-PK's kinase activity 27,28 which phosphorylates H2AX to form γH2AX. …”

confidence: 99%

“…The resultant DNA-PK complex activates DNA-PK's kinase activity 27,28 which phosphorylates H2AX to form γH2AX. It also facilitates the recruitment of a ligation complex, which encompasses DNA LigIV and XRCC4 among other proteins.…”

confidence: 99%

BRCC3 mutations in myeloid neoplasms

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o nUIMC1, FAM175A, BABAM1, BRE, BARD1, BRCC3 and BRCA1 and participates in DNA double-strand break (DSB) repair. 17 DSBs are associated with genomic instability, cell death 18 and carcinogenesis. 19 To repair DSBs, cells use both homologous recombination (HR), which uses sister-chromatid alleles as templates in late S and G 2 , and non-homologous end joining (NHEJ) which can operate in all phases of the cell cycle but often leaves small deletions, possibly gene inactivating at the site of repair. 20 The BRISC complex comprises the following proteins: FAM175B/ABRO1, BRCC3/BRCC36, BRE/BRCC45 and MERIT40/NBA1.Here, we report that somatic defects of BRCC3 are acquired in various myeloid neoplasms and have consequences at the cellular, and perhaps the clinical level. Methods PatientsBone marrow aspirates or blood were collected from the patients with various myeloid neoplasms seen at the Cleveland Clinic, University of Tokyo and Münchner Leukämielabor GmbH (MLL) (Online Supplementary Table S1). Informed consent for sample collection was obtained according to protocols approved by the institutional review boards in accordance with the Declaration of Helsinki. Diagnoses were confirmed according to 2008 World Health Organization classification criteria. 21 A total of 1778 patients were enrolled in this study (Online Supplementary Table S1). Next generation sequencingWhole exome sequencing (WES) was performed as previously reported. 4,6 Briefly, tumor DNAs were extracted from patients' bone marrow cells. For germ-line controls, DNA was obtained from paired CD3 + T cells. For targeted detection of sequence alterations, confirmation of WES and assessment of variant allelic frequency (VAF), we applied deep sequencing to targeted exons, as previously described. 6,22 Briefly, each targeted exon was amplified with each pair of primers, generating 200bp fragments on average. These amplicons were subjected to massive parallel sequencing (Illumina, San Diego, CA, USA) using TruSeq custom primers (Illumina) and SureSelect (Agilent, Santa Clara, CA, USA) with paired-end reads, according to the manufacture's instruction. Some of these procedures were followed by confirmation using Sanger sequencing, as previously described. 13 Annotations by NCBI reference numbers of the genes affected by somatic mutations are summarized in Online Supplementary Table S2. Cytogenetics and single nucleotide polymorphism-array analysesTechnical details about sample processing and data analyses for single nucleotide polymorphism-array (SNP-A) have been previously described.23 Affymetrix 250K and 6.0 Kit (Affymetrix) were used. Germ-line copy number variants in our internal database or in a publicly available database (Database of Genomic Variants) (http://dgv.tcag.ca/dgv/app/home) were considered non-somatic variants and excluded. Results were analyzed with CNAG (v.3.0) 24 or Genotyping Console (Affymetrix). All other lesions were confirmed as somatic or germ-line by analysis of CD3-sorted cells. Sh...

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DNA DSB repair pathway choice: an orchestrated handover mechanism

Cited by 237 publications

References 61 publications

Extracellular ATP protects endothelial cells against DNA damage

Extracellular ATP protects endothelial cells against DNA damage

Nucleolin and nucleophosmin: nucleolar proteins with multiple functions in DNA repair

BRCC3 mutations in myeloid neoplasms

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