Abstract:
:The alternative non-homologous end-joining (NHEJ) machinery facilitates several genomic rearrangements, some of which can lead to cellular transformation. This error-prone repair pathway is triggered upon telomere de-protection to promote the formation of deleterious chromosome end-to-end fusions. Using next-generation sequencing technology, here we show that repair by alternative NHEJ yields non-TTAGGG nucleotide insertions at fusion breakpoints of dysfunctional telomeres. Investigating the enzymatic activity responsible for the random insertions enabled us to identify polymerase theta (Polθ; encoded by Polq in mice) as a crucial alternative NHEJ factor in mammalian cells. Polq inhibition suppresses alternative NHEJ at dysfunctional telomeres, and hinders chromosomal translocations at non-telomeric loci. In addition, we found that loss of Polq in mice results in increased rates of homology-directed repair, evident by recombination of dysfunctional telomeres and accumulation of RAD51 at double-stranded breaks. Lastly, we show that depletion of Polθ has a synergistic effect on cell survival in the absence of BRCA genes, suggesting that the inhibition of this mutagenic polymerase represents a valid therapeutic avenue for tumours carrying mutations in homology-directed repair genes.
journal_name
Naturejournal_title
Natureauthors
Mateos-Gomez PA,Gong F,Nair N,Miller KM,Lazzerini-Denchi E,Sfeir Adoi
10.1038/nature14157subject
Has Abstractpub_date
2015-02-12 00:00:00pages
254-7issue
7538eissn
0028-0836issn
1476-4687pii
nature14157journal_volume
518pub_type
杂志文章相关文献
NATURE文献大全abstract::Establishing the age at death of individuals is an important step in their identification and can be done with high precision up to adolescence by analysis of dentition, but it is more difficult in adults. Here we show that the amount of radiocarbon present in tooth enamel as a result of nuclear bomb testing during 19...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/437333a
更新日期:2005-09-15 00:00:00
abstract::The emergence of HIV-1 group M subtype B in North American men who have sex with men was a key turning point in the HIV/AIDS pandemic. Phylogenetic studies have suggested cryptic subtype B circulation in the United States (US) throughout the 1970s and an even older presence in the Caribbean. However, these temporal an...
journal_title:Nature
pub_type: 历史文章,杂志文章
doi:10.1038/nature19827
更新日期:2016-11-03 00:00:00
abstract::Landscapes modified by glacial erosion show a distinct distribution of surface area with elevation (hypsometry). In particular, the height of these regions is influenced by climatic gradients controlling the altitude where glacial and periglacial processes are the most active, and as a result, surface area is focused ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature11786
更新日期:2013-01-10 00:00:00
abstract::Homeostatic mechanisms in mammals respond to hormones and nutrients to maintain blood glucose levels within a narrow range. Caloric restriction causes many changes in glucose metabolism and extends lifespan; however, how this metabolism is connected to the ageing process is largely unknown. We show here that the Sir2 ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature03354
更新日期:2005-03-03 00:00:00
abstract::The origin and growth of magnetic fields in galaxies is still something of an enigma. It is generally assumed that seed fields are amplified over time through the dynamo effect, but there are few constraints on the timescale. It was recently demonstrated that field strengths as traced by rotation measures of distant (...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature07105
更新日期:2008-07-17 00:00:00
abstract::A brief account is provided of a meeting between federal officials and representatives of the Industrial Biotechnology Association (IBA), a consortium of companies concerned about the regulatory outlook for their industry. Current regulatory interest is focused on the Environmental Protection Agency, which has declar...
journal_title:Nature
pub_type: 新闻
doi:10.1038/305755a0
更新日期:1983-10-27 00:00:00
abstract::Monoclonal antibodies were raised against antibodies to distinct carboxy-terminal KDEL sequences of two soluble, resident endoplasmic reticulum proteins. These anti-idiotype reagents recognize an intrinsic membrane protein with characteristics expected of a receptor responsible for the recognition and return of reside...
journal_title:Nature
pub_type: 杂志文章,收录出版
doi:10.1038/345495a0
更新日期:1990-06-07 00:00:00
abstract::Animal behaviour arises from computations in neuronal circuits, but our understanding of these computations has been frustrated by the lack of detailed synaptic connection maps, or connectomes. For example, despite intensive investigations over half a century, the neuronal implementation of local motion detection in t...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature12450
更新日期:2013-08-08 00:00:00
abstract::An unusual feature of the cerebellar cortex is that its output neurons, Purkinje cells, release GABA (γ-aminobutyric acid). Their high intrinsic firing rates (50 Hz) and extensive convergence predict that their target neurons in the cerebellar nuclei would be largely inhibited unless Purkinje cells pause their spiking...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature10732
更新日期:2011-12-25 00:00:00
abstract::Recent studies have suggested that actomyosin threads may provide a useful model for studying the properties of contractile systems. The development of highly sensitive positional feedback transducers has enabled the properties of these threads to be measured reproducibly. Potential applications include such systems a...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/287338a0
更新日期:1980-09-25 00:00:00
abstract::Injury causes a systemic inflammatory response syndrome (SIRS) that is clinically much like sepsis. Microbial pathogen-associated molecular patterns (PAMPs) activate innate immunocytes through pattern recognition receptors. Similarly, cellular injury can release endogenous 'damage'-associated molecular patterns (DAMPs...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature08780
更新日期:2010-03-04 00:00:00
abstract::How the brain selects appropriate sensory inputs and suppresses distractors is unknown. Given the well-established role of the prefrontal cortex (PFC) in executive function, its interactions with sensory cortical areas during attention have been hypothesized to control sensory selection. To test this idea and, more ge...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature15398
更新日期:2015-10-29 00:00:00
abstract::The rat hippocampus receives a strong cholinergic innervation from the medial septum; information about the development and function of this pathway could help to elucidate the mechanisms of memory functions. Previous electrophysiological studies have shown that septal stimulation in vivo facilitates commissural and p...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/313577a0
更新日期:1985-02-14 00:00:00
abstract::One goal of regenerative medicine, to use stem cells to replace cells lost by injury or disease, depends on producing an excess of the relevant cell for study or transplantation. To this end, the stepwise differentiation of stem cells into specialized derivatives has been successful for some cell types, but a major pr...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature11463
更新日期:2012-11-29 00:00:00
abstract::The tumour microenvironment may contribute to tumorigenesis owing to mechanical forces such as fibrotic stiffness or mechanical pressure caused by the expansion of hyper-proliferative cells. Here we explore the contribution of the mechanical pressure exerted by tumour growth onto non-tumorous adjacent epithelium. In t...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature14329
更新日期:2015-07-02 00:00:00
abstract::On 12 May 2008, the devastating magnitude 7.9 (Wenchuan) earthquake struck the eastern edge of the Tibetan plateau, collapsing buildings and killing thousands in major cities aligned along the western Sichuan basin in China. After such a large-magnitude earthquake, rearrangement of stresses in the crust commonly leads...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature07177
更新日期:2008-07-24 00:00:00
abstract::A CENTRAL assumption about long-term potentiation in the hippocampus is that the two classes of glutamate-receptor ion channel, the N-methyl-D-aspartate (NMDA) and the kainate/quisqualate (non-NMDA) subtypes, are co-localized at individual excitatory synapses. This assumption is important because of the perceived inte...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/341230a0
更新日期:1989-09-21 00:00:00
abstract::HIV has advanced from high-risk groups such as intravenous drug users to some in the general population, according to comprehensive new data from the south of China. What needs to be done to halt its spread? ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/455609a
更新日期:2008-10-02 00:00:00
abstract::Recent work has identified a neuron with widespread projections to odour processing regions of the honeybee brain whose activity represents the reward value of gustatory stimuli. We have constructed a model of bee foraging in uncertain environments based on this type of neuron and a predictive form of hebbian synaptic...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/377725a0
更新日期:1995-10-26 00:00:00
abstract::Increasing population and consumption are placing unprecedented demands on agriculture and natural resources. Today, approximately a billion people are chronically malnourished while our agricultural systems are concurrently degrading land, water, biodiversity and climate on a global scale. To meet the world's future ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature10452
更新日期:2011-10-12 00:00:00
abstract::Protein aggregates are the hallmark of stressed and ageing cells, and characterize several pathophysiological states. Healthy metazoan cells effectively eliminate intracellular protein aggregates, indicating that efficient disaggregation and/or degradation mechanisms exist. However, metazoans lack the key heat-shock p...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature14884
更新日期:2015-08-13 00:00:00
abstract::Vasopressin (VP) potentiates the effect of corticotropin-releasing factor (CRF) on the secretion of adrenocorticotropic hormone (ACTH) from anterior pituitary cells in vitro, and both CRF and VP have been found in portal blood. These data support the hypothesis that VP acts synergistically with CRF to cause the secret...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/317248a0
更新日期:1985-09-19 00:00:00
abstract::Is the big-bang hot, warm or cold? And are galactic masses determined by the interplay of gravitational and strong interactions in the very early universe? ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/228258a0
更新日期:1970-10-17 00:00:00
abstract::Double-walled carbon nanotubes are needed in a pure, highly crystalline form before features such as their electronic properties, thermal transport and mechanical behaviour can be investigated. Here we fabricate a paper-like material that consists of hexagonally packed bundles of clean, coaxial carbon nanotubes whose ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/433476a
更新日期:2005-02-03 00:00:00
abstract::The B cells of the immune system, which secrete antibodies against foreign antigens, are fully specific and effective only after maturation in lymph nodes and other lymphoid tissues. Immunocompetent T cells play a crucial part in this process, but the molecular details of the way in which the two cell types interact h...
journal_title:Nature
pub_type: 杂志文章,评审
doi:10.1038/367425a0
更新日期:1994-02-03 00:00:00
abstract::Deep neural networks have achieved impressive successes in fields ranging from object recognition to complex games such as Go1,2. Navigation, however, remains a substantial challenge for artificial agents, with deep neural networks trained by reinforcement learning3-5 failing to rival the proficiency of mammalian spat...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-018-0102-6
更新日期:2018-05-01 00:00:00
abstract::Genetic models predict that genomic rearrangement in hybrids can facilitate reproductive isolation and the formation of new species by preventing gene flow between the parent species and hybrid (sunflowers are an example). The mechanism underlying hybridization-induced chromosome remodelling is as yet unknown, althoug...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/29985
更新日期:1998-05-07 00:00:00
abstract::Global efforts to mitigate climate change are guided by projections of future temperatures. But the eventual equilibrium global mean temperature associated with a given stabilization level of atmospheric greenhouse gas concentrations remains uncertain, complicating the setting of stabilization targets to avoid potenti...
journal_title:Nature
pub_type: 历史文章,杂志文章
doi:10.1038/nature08019
更新日期:2009-04-30 00:00:00
abstract::Large seasonal and hemispheric asymmetries in the martian climate system are generally ascribed to variations in solar heating associated with orbital eccentricity. As the orbital elements slowly change (over a period of >104 years), characteristics of the climate such as dustiness and the vigour of atmospheric circul...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/416298a
更新日期:2002-03-21 00:00:00
abstract::The Gulf Stream transports large amounts of heat from the tropics to middle and high latitudes, and thereby affects weather phenomena such as cyclogenesis and low cloud formation. But its climatic influence, on monthly and longer timescales, remains poorly understood. In particular, it is unclear how the warm current ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature06690
更新日期:2008-03-13 00:00:00