Brca1 is required for DNA repair by homologous recombination (HR) and normal embryonic development. Here we report that deletion of the DNA damage response factor 53BP1 overcomes embryonic lethality ...in Brca1-nullizygous mice and rescues HR deficiency, as measured by hypersensitivity to polyADP-ribose polymerase (PARP) inhibition. However, Brca1,53BP1 double-deficient cells are hypersensitive to DNA interstrand crosslinks (ICLs), indicating that BRCA1 has an additional role in DNA crosslink repair that is distinct from HR. Disruption of the nonhomologous end-joining (NHEJ) factor, Ku, promotes DNA repair in Brca1-deficient cells; however deletion of either Ku or 53BP1 exacerbates genomic instability in cells lacking FANCD2, a mediator of the Fanconi anemia pathway for ICL repair. BRCA1 therefore has two separate roles in ICL repair that can be modulated by manipulating NHEJ, whereas FANCD2 provides a key activity that cannot be bypassed by ablation of 53BP1 or Ku.
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► DNA crosslink repair is regulated by two separate activities of BRCA1 ► Ku antagonizes HR by promoting NHEJ, whereas 53BP1 inhibits DNA end resection ► 53BP1 deletion rescues embryonic development in BRCA1 nullizygous mice ► Ku deletion exacerbates development defects and instability in FANCD2−/− mice
ATRX, a guardian of chromatin Aguilera, Paula; López-Contreras, Andrés J.
Trends in genetics,
June 2023, 2023-06-00, 20230601, Volume:
39, Issue:
6
Journal Article
Peer reviewed
Open access
ATRX controls the expression of several regions of the genome. ATRX represses difficult-to-replicate regions such as pericentromeric or telomeric heterochromatin, activates transcription of ...particular euchromatic regions such as the α-globin locus, and contributes to the silencing of the inactive X chromosome.ATRX is a central player regulating the DNA damage response and prevents chromosomal instability. ATRX limits the formation of secondary structures that can trigger replication fork stalling and replication stress. Furthermore, ATRX regulates DNA repair via homologous recombination.ATRX mutations are highly frequent in glioma and other cancers. ATRX mutations induce the ALT pathway and may affect chromosomal stability and senescence. Thus, ATRX deficiency influences the response to cancer therapies and may be exploited to develop new cancer treatments.
ATRX (alpha-thalassemia mental retardation X-linked) is one of the most frequently mutated tumor suppressor genes in human cancers, especially in glioma, and recent findings indicate roles for ATRX in key molecular pathways, such as the regulation of chromatin state, gene expression, and DNA damage repair, placing ATRX as a central player in the maintenance of genome stability and function. This has led to new perspectives about the functional role of ATRX and its relationship with cancer. Here, we provide an overview of ATRX interactions and molecular functions and discuss the consequences of its impairment, including alternative lengthening of telomeres and therapeutic vulnerabilities that may be exploited in cancer cells.
The relentless role of invasive species in the extinction of native biota requires predictions of ecosystem vulnerability to inform proactive management strategies. The worldwide invasion and range ...expansion of predatory northern pike (
Esox lucius
) has been linked to the decline of native fishes and tools are needed to predict the vulnerability of habitats to invasion over broad geographic scales. To address this need, we coupled an intrinsic potential habitat modelling approach with a Bayesian network to evaluate the vulnerability of five culturally and economically vital species of Pacific salmon (
Oncorhynchus
spp.) to invasion by northern pike. This study was conducted along 22,875 stream km in the Southcentral region of Alaska, USA. Pink salmon (
O
.
gorbuscha
) were the most vulnerable species, with 15.2% (2,458 km) of their calculated extent identified as “highly” vulnerable, followed closely by chum salmon (
O
.
keta
, 14.8%; 2,557 km) and coho salmon (
O
.
kisutch
, 14.7%; 2,536 km). Moreover, all five Pacific salmon species were highly vulnerable in 1,001 stream km of shared habitat. This simple to implement, adaptable, and cost-effective framework will allow prioritizing habitats for early detection and monitoring of invading northern pike.
Warming and drought are reducing global crop production with a potential to substantially worsen global malnutrition. As with the green revolution in the last century, plant genetics may offer ...concrete opportunities to increase yield and crop adaptability. However, the rate at which the threat is happening requires powering new strategies in order to meet the global food demand. In this review, we highlight major recent ‘big data’ developments from both empirical and theoretical genomics that may speed up the identification, conservation, and breeding of exotic and elite crop varieties with the potential to feed humans. We first emphasize the major bottlenecks to capture and utilize novel sources of variation in abiotic stress (i.e., heat and drought) tolerance. We argue that adaptation of crop wild relatives to dry environments could be informative on how plant phenotypes may react to a drier climate because natural selection has already tested more options than humans ever will. Because isolated pockets of cryptic diversity may still persist in remote semi-arid regions, we encourage new habitat-based population-guided collections for genebanks. We continue discussing how to systematically study abiotic stress tolerance in these crop collections of wild and landraces using geo-referencing and extensive environmental data. By uncovering the genes that underlie the tolerance adaptive trait, natural variation has the potential to be introgressed into elite cultivars. However, unlocking adaptive genetic variation hidden in related wild species and early landraces remains a major challenge for complex traits that, as abiotic stress tolerance, are polygenic (i.e., regulated by many low-effect genes). Therefore, we finish prospecting modern analytical approaches that will serve to overcome this issue. Concretely, genomic prediction, machine learning, and multi-trait gene editing, all offer innovative alternatives to speed up more accurate pre- and breeding efforts toward the increase in crop adaptability and yield, while matching future global food demands in the face of increased heat and drought. In order for these ‘big data’ approaches to succeed, we advocate for a trans-disciplinary approach with open-source data and long-term funding. The recent developments and perspectives discussed throughout this review ultimately aim to contribute to increased crop adaptability and yield in the face of heat waves and drought events.
Genome-environment associations (GEAs) are a powerful strategy for the study of adaptive traits in wild plant populations, yet they still lack behind in the use of modern statistical methods as the ...ones suggested for genome-wide association studies (GWASs). In order to bridge this gap, we couple GEA with last-generation GWAS algorithms in common bean to identify novel sources of heat tolerance across naturally heterogeneous ecosystems. Common bean (
L.) is the most important legume for human consumption, and breeding it for resistance to heat stress is key because annual increases in atmospheric temperature are causing decreases in yield of up to 9% for every 1°C. A total of 78 geo-referenced wild accessions, spanning the two gene pools of common bean, were genotyped by sequencing (GBS), leading to the discovery of 23,373 single-nucleotide polymorphism (SNP) markers. Three indices of heat stress were developed for each accession and inputted in last-generation algorithms (
SUPER, FarmCPU, and BLINK) to identify putative associated loci with the environmental heterogeneity in heat stress. Best-fit models revealed 120 significantly associated alleles distributed in all 11 common bean chromosomes. Flanking candidate genes were identified using 1-kb genomic windows centered in each associated SNP marker. Some of these genes were directly linked to heat-responsive pathways, such as the activation of heat shock proteins (
,
,
,
, and
). We also found protein domains related to thermostability in plants such as
and
and
. Other genes were related to biological processes that may correlate with plant tolerance to high temperature, such as time to flowering (
,
, and
), germination and seedling development (
,
, and
), cell wall stability (
), and signaling pathway of abiotic stress via abscisic acid (histone-like transcription factors
and
) and auxin (
and
). This work offers putative associated loci for marker-assisted and genomic selection for heat tolerance in common bean. It also demonstrates that it is feasible to identify genome-wide environmental associations with modest sample sizes by using a combination of various carefully chosen environmental indices and last-generation GWAS algorithms.
Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by progerin, a mutant lamin A variant. HGPS patients display accelerated aging and die prematurely, typically from ...atherosclerosis complications. Recently, we demonstrated that progerin‐driven vascular smooth muscle cell (VSMC) loss accelerates atherosclerosis leading to premature death in apolipoprotein E‐deficient mice. However, the molecular mechanism underlying this process remains unknown. Using a transcriptomic approach, we identify here endoplasmic reticulum stress (ER) and the unfolded protein responses as drivers of VSMC death in two mouse models of HGPS exhibiting ubiquitous and VSMC‐specific progerin expression. This stress pathway was also activated in HGPS patient‐derived cells. Targeting ER stress response with a chemical chaperone delayed medial VSMC loss and inhibited atherosclerosis in both progeria models, and extended lifespan in the VSMC‐specific model. Our results identify a mechanism underlying cardiovascular disease in HGPS that could be targeted in patients. Moreover, these findings may help to understand other vascular diseases associated with VSMC death, and provide insight into aging‐dependent vascular damage related to accumulation of unprocessed toxic forms of lamin A.
Synopsis
In mouse models of Hutchinson–Gilford progeria syndrome (HGPS) featuring ubiquitous or vascular smooth muscle cell (VSMC)‐specific progerin expression, RNA sequencing of medial aortas identified a new pathway involved in the etiopathology of the disease.
Activation of endoplasmic reticulum (ER) stress and of the unfolded protein response (UPR) was observed prior signs of vascular disease in VSMC‐rich aortic media from mouse models of HGPS.
ER stress and the UPR were activated in cultured cells derived from HGPS patients and in some organs of the ubiquitous HGPS mouse model.
VSMC loss was ameliorated and atherosclerosis was prevented in the HGPS mouse models upon tauroursodeoxycholic acid (TUDCA) treatment.
VSMC‐specific progeroid mice survival was prolonged by TUDCA, demonstrating its potential as a treatment for vascular disease in HGPS.
In mouse models of Hutchinson–Gilford progeria syndrome (HGPS) featuring ubiquitous or vascular smooth muscle cell (VSMC)‐specific progerin expression, RNA sequencing of medial aortas identified a new pathway involved in the etiopathology of the disease.
Progerin, an aberrant protein that accumulates with age, causes the rare genetic disease Hutchinson-Gilford progeria syndrome (HGPS). Patients who have HGPS exhibit ubiquitous progerin expression, ...accelerated aging and atherosclerosis, and die in their early teens, mainly of myocardial infarction or stroke. The mechanisms underlying progerin-induced atherosclerosis remain unexplored, in part, because of the lack of appropriate animal models.
We generated an atherosclerosis-prone model of HGPS by crossing apolipoprotein E-deficient (
) mice with
mice ubiquitously expressing progerin. To induce progerin expression specifically in macrophages or vascular smooth muscle cells (VSMCs), we crossed
mice with
and
mice, respectively. Progerin expression was evaluated by polymerase chain reaction and immunofluorescence. Cardiovascular alterations were determined by immunofluorescence and histology in male mice fed normal chow or a high-fat diet. In vivo low-density lipoprotein retention was assessed by intravenous injection of fluorescently labeled human low-density lipoprotein. Cardiac electric defects were evaluated by electrocardiography.
mice with ubiquitous progerin expression exhibited a premature aging phenotype that included failure to thrive and shortened survival. In addition, high-fat diet-fed
mice developed a severe vascular pathology, including medial VSMC loss and lipid retention, adventitial fibrosis, and accelerated atherosclerosis, thus resembling most aspects of cardiovascular disease observed in patients with HGPS. The same vascular alterations were also observed in
mice expressing progerin specifically in VSMCs, but not in
mice with macrophage-specific progerin expression. Moreover,
mice had a shortened lifespan despite the lack of any overt aging phenotype. Aortas of ubiquitously and VSMC-specific progerin-expressing mice exhibited increased retention of fluorescently labeled human low-density lipoprotein, and atheromata in both models showed vulnerable plaque features. Immunohistopathological examination indicated that
mice, unlike
mice, die of atherosclerosis-related causes.
We have generated the first mouse model of progerin-induced atherosclerosis acceleration, and demonstrate that restricting progerin expression to VSMCs is sufficient to accelerate atherosclerosis, trigger plaque vulnerability, and reduce lifespan. Our results identify progerin-induced VSMC death as a major factor triggering atherosclerosis and premature death in HGPS.
Molecular evolution offers an insightful theory to interpret the genomic consequences of thermal adaptation to previous events of climate change beyond range shifts. However, disentangling often ...mixed footprints of selective and demographic processes from those due to lineage sorting, recombination rate variation, and genomic constrains is not trivial. Therefore, here we condense current and historical population genomic tools to study thermal adaptation and outline key developments (genomic prediction, machine learning) that might assist their utilization for improving forecasts of populations' responses to thermal variation. We start by summarizing how recent thermal-driven selective and demographic responses can be inferred by coalescent methods and in turn how quantitative genetic theory offers suitable multi-trait predictions over a few generations via the breeder's equation. We later assume that enough generations have passed as to display genomic signatures of divergent selection to thermal variation and describe how these footprints can be reconstructed using genome-wide association and selection scans or, alternatively, may be used for forward prediction over multiple generations under an infinitesimal genomic prediction model. Finally, we move deeper in time to comprehend the genomic consequences of thermal shifts at an evolutionary time scale by relying on phylogeographic approaches that allow for reticulate evolution and ecological parapatric speciation, and end by envisioning the potential of modern machine learning techniques to better inform long-term predictions. We conclude that foreseeing future thermal adaptive responses requires bridging the multiple spatial scales of historical and predictive environmental change research under modern cohesive approaches such as genomic prediction and machine learning frameworks.
Replication comes with a price. The molecular gymnastics that occur on DNA during its duplication frequently derive to a wide spectrum of abnormalities which are still far from understood. These are ...brought together under the unifying term “replicative stress” (RS) which likely stands for large and unprotected regions of single-stranded DNA (ssDNA). In addition to RS, recombinogenic stretches of ssDNA are also formed at resected DNA double strand breaks (DSBs). Both situations converge on a ssDNA intermediate, which is the triggering signal for a damage situation. The cellular response in both cases is coordinated by a phosphorylation-based signaling cascade that starts with the activation of the ATR (ATM and Rad3-related) kinase. Given that ATR is essential for replicating cells, understanding the consequences of a defective ATR response for a mammalian organism has been limited until recent years. We here discuss on the topic and review the findings that connect ATR to ageing and cancer.
Mint (
L., Lamiaceae) is a strongly scented herb of the family Lamiaceae that is grown mostly by clonal propagation, making it a valuable species for the study of somaclonal variation and its ...phenotypic consequences. The recent introduction of a few species of mint in South America, followed by a presumably rampant propagation, make this region particularly ideal for studying the extent of somaclonal genetic diversity. Hence, the objective of this work was to offer a preliminary characterization of somaclonal genetically coding diversity of the mint in the northern Andes in order to address the question of whether somaclonal variants may have emerged despite relatively recent introductions in a region where mint is not native. A total of 29 clonally propagated specimens, collected in mint export farms in the province of Antioquia, a major region for mint production in the northwest Andes of Colombia, were genotyped using RNA sequencing (RNA-Seq). SNP calling was carried out from the leaves' transcriptome profiles of each plant by combining the GATK4 and TRINITY protocols, obtaining a total of 2033 loci across 912 transcripts with a minimum read depth of 20X and 4% of missing data. Unsupervised machine learning algorithms considered the
-means, AGNES and UPGMA approaches, all of which suggested three genetic clusters for
and a unique cluster for
. The results indicate that at least two different origins of
reached the eastern region of the Antioquia province, clonally propagated in the locality ever since for local consumption and export. One of these ancestries had more population structure, possibly due to environmental or anthropological pressures that intervened in the fragmentation of this genetic group or to a higher somaclonal mutation rate. This work offers a first step into the study of the accumulation and transmission of presumably quasi-neutral somatic mutations at coding regions in an herbaceous clonally propagated scented species such as mint, likely favored by an expected population expansion after its Andean introduction. These ad hoc hypotheses warrant further study as part of future research.
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