XRN2 Links Transcription Termination to DNA Damage and Replication Stress

We thank the Proteomics Core Facility. We thank Dr. Robert J. Crouch for providing us with GFP- and GFP-RNase H expression plasmids. We also thank Dr. Stephen H. Leppla for providing us with antibodies directed against RNA:DNA hybrids (R loops) (S9.6). We thank Novus Biologicals for generously providing XRN2 and Rrp45 antibodies. We also thank the members of the Boothman lab for critical reading of this manuscript.Author Summary Genomic instability is one of the primary causes of disease states, in particular cancer. One major cause of genomic instability is the formation of DNA double strand breaks (DSBs), which are one of the most dangerous types of DNA lesions the cell can encounter. If not repaired in a timely manner, one DSB can lead not only to cell death. If misrepaired, one DSB can lead to a hazardous chromosomal aberration, such as a translocation, that can eventually lead to cancer. The cell encounters and repairs DSBs that arise from naturally occurring cellular processes on a daily basis. A number of studies have demonstrated that aberrant structures that form during transcription under certain circumstances, in particular RNA:DNA hybrids (R loops), can lead to DSB formation and genomic instability, especially during DNA synthesis. Thus, it is important to understand how the cell responds and repairs transcription-mediated DNA damage in general and R loop-related DNA damage in particular. This paper both demonstrates that the XRN transcription termination factor links transcription and DNA damage, but also provides a better understanding of how the cell prevents transcription-related DNA damage.Yeshttp://www.plosgenetics.org/static/editorial#pee

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.</p

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Serial search for targets defined by divergence or deformation of optic flow.

The optic flow field can be described in terms of the local differential measures, divergence, deformation, and rotation, which are informative about observer motion and the 3-D structure of the environment. Does an explicit representation of these measures exist in human visual processing in the form of a feature map? Triesman's criteria were used to investigate this; ie is there 'pop-out' for a target defined as different in local divergence or deformation from surrounding elements, or is a serial search necessary? The stimulus arrays contained 3, 5, or 9 square or rectangular elements, which each underwent repeated cycles of expansion, contraction, or deformation. The time required to detect a target undergoing the opposite transformation increased steeply with the number of elements, implying very slow serial search. (The mean time was 210 ms per element for divergence targets and 542 ms per element for deformation). The process was clearly still serial when the density and number of elements was increased up to 48 in an array 2.16 deg x 2.16 deg. In contrast, a single line element undergoing the opposite direction of translation motion to the rest of the display did show pop-out. It is concluded that no parallel processes seem to exist which are sensitive to the spatial uniformity of divergence and of deformation of optic flow. These differential properties may be derived as conjunctions of signals from a primary process which extracts local velocity. This result contrasts with our findings for targets defined by stereo disparity gradient, which show parallel processing in analogous experiments

Pre-attentive detection of a target defined by stereoscopic slant.

Does the visual system represent stereoscopic depth purely as a map of local disparities, or does it explicitly represent local relationships of disparity, such as disparity gradients? Experiments are reported in which visual search for a target containing the same disparity range as other elements in the display, but differing in the relationship of the disparities (stereo slant), was used to determine whether the target showed 'pop-out' like a unitary feature, or the serial search characteristic of feature conjunctions. Each stereo pair of elements was selected randomly from a range of outline parallelograms leaning to the right or to the left, so that the target could not be identified using any monocular shape cue. Response times for detection of the target (present on 50% of the trials) were independent of the number of elements in the display. This result was confirmed by varying element size and spacing, and by using oblique crosses rather than parallelograms as stimuli. It is concluded that stereoscopically defined slant, or disparity gradient, can be processed and compared in parallel across the display, and acts in this respect as an explicit unitary visual property. This contrasts with findings in analogous experiments on movement, which show that targets defined by divergence or deformation of optic flow can only be identified by serial search

From DNA- to NA-centrism and the conditions for gene-centrism revisited

First the 'Weismann barrier' and later on Francis Crick's 'central dogma' of molecular biology nourished the gene-centric paradigm of life, i.e., the conception of the gene/genome as a 'central source' from which hereditary specificity unidirectionally flows or radiates into cellular biochemistry and development. Today, due to advances in molecular genetics and epigenetics, such as the discovery of complex post-genomic and epigenetic processes in which genes are causally integrated, many theorists argue that a gene-centric conception of the organism has become problematic. Here, we first explore the causal implications of the following two central dogma-related issues: (1) widespread reverse transcription-arguing for an extension from 'DNA-genome' to RNA-encompassing 'NA-genome' and, thus, from traditional DNA-centrism to a broader 'NA-centrism'; and (2) the absence of a mechanism of reverse translation-arguing for the 'structural primacy' of NA-sequence over protein in cellular biochemistry. Secondly, we explore whether this latter conclusion can be extended to a 'functional primacy' of NA-sequence over protein in cellular biochemistry, which would imply a limited kind of 'gene/NA-centrism' confined to the subcellular level of NA/protein-based biochemistry. Finally, we explore the conditions-and their (non)fulfilment-for a more generalised form of gene-centrism extendable to higher levels of biological organisation. We conclude that the higher we go in the biological hierarchy, the more dubious gene-centric claims become