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At least 973 records · Page 54Linked to original sources
PubMed2003

DNA double strand breaks (DSB) and non-homologous end joining (NHEJ) pathways in human leukemia.

DNA double strand breaks (DSB) are considered the most lethal form of DNA damage for eukaryotic cells. DSB can either be properly repaired, restoring genomic integrity, or misrepaired resulting in drastic consequences, such as cell death, genomic instability, and cancer. It is well established that exposure to DSB-inducing agents is associated with chromosomal abnormalities and leukemogenesis. The non-homologous end joining (NHEJ) pathway is considered a major route for the repair DSB in mammalian cells. Although the mechanism(s) by which repair of DSB lead to leukemia are poorly understood, recent evidence is beginning to emerge that a poorly defined and error-prone branch of the NHEJ pathway plays a pivotal role in this process. This review discusses some of the ways in which error-prone NHEJ repair may be involved in the development of genomic instability and leukemia.

Animals↗
PubMed2007

The multi-step process of human skin carcinogenesis: a role for p53, cyclin D1, hTERT, p16, and TSP-1.

As proposed by Hanahan and Weinberg (2000. Cell 100, 57-70) carcinogenesis requires crucial events such as (i) genomic instability, (ii) cell cycle deregulation, (iii) induction of a telomere length maintenance mechanism, and (iv) an angiogenic switch. By comparing the expression of p53, cyclin D1, p16, hTERT, and TSP-1 in spontaneously regressing keratoacanthoma (KA) as a paradigm of early neoplasia, with malignant invasive cutaneous squamous cell carcinoma (SCC) as a paradigm of advanced tumour development, we are now able to assign the changes in the expression of these proteins to specific stages and allocate them to defined roles in the multi-step process of skin carcinogenesis. We show that mutational inactivation of the p53 gene, and with that the onset of genomic instability is the earliest event. Individual p53-positive cells are already seen in "normal" skin, and 3/5 actinic keratoses (AKs), 5/22 KAs, and 13/23 SCCs contain p53-positive patches. Cell cycle deregulation was indicated by the overexpression of the cell cycle regulator cyclin D1, as well as by the loss of the cell cycle inhibitor p16. Interestingly, overexpression of cyclin D1 - observed in 80% of KAs and SCCs, respectively - showed a cell cycle-independent function in HaCaT cell transplants on nude mice. Cyclin D1 overexpression was associated with a massive inflammatory response, finally leading to tissue destruction. Loss of the cell cycle inhibitor p16, on the other hand, correlated with SCCs. Thus, it is tempting to suggest that overexpression of cyclin D1 is an early change that in addition to growth stimulation leads to an altered epithelial-mesenchymal interaction, while functional p16 is able to control this deregulated growth and needs to be eliminated for malignant progression. Another requirement for uncontrolled growth is the inhibition of telomere erosion by up-regulating telomerase activity. As measured by hTERT protein expression, all of the KAs and SCCs studied were positive, with a similar distribution of the protein in both groups and an expression pattern resembling that of normal epidermis. Thus, telomerase may not need to be increased significantly in skin carcinomas. Finally, we show that the angiogenesis inhibitor TSP-1 is strongly expressed in most KAs, and mainly by the tumour cells, while in SCCs the generally weak expression is restricted to the tumour-stroma. Furthermore, we provide evidence that the loss of a copy of chromosome 15 is responsible for reduced TSP-1 expression and thereby this aberration contributes to tumour vascularisation (i.e. the angiogenic switch) required for malignant growth.

Animals↗
PubMed2001

Temporal delineation of sequential HPRT mutations arising in vivo in a T-cell clone with a mutator phenotype.

Recurrent mutations in vivo in T-lymphocytes identify clonally restricted genomic instabilities in some individuals. Cell-based assays allow initial recognition of clones with mutator phenotypes, but genotypic selection is required to determine frequencies and temporal sequences of potentially independent mutational events isolated only as complex changes in the same allele. The present work illustrates how two single-base insertions in the HPRT gene recovered only as a double event in a cell-based assay were shown to arise as separate in vivo mutations, being individually present at frequencies of < or =10(-4) and < or =10(-5), respectively, in peripheral blood. Full characterizations of mutator clones will allow elucidation of the earliest events in the emergence of genomic instability in human somatic cells.

Adult↗
PubMed1996

Antisense GADD45 expression results in decreased DNA repair and sensitizes cells to u.v.-irradiation or cisplatin.

Loss of p53 function in cancer cells commonly results in a condition of genomic instability. This is believed to emanate from a loss of the G1 checkpoint response to DNA damage. While the role of p53 in the induction of a G1 arrest is well-accepted, additional p53 functions are being discovered. Cell cycle checkpoints presumably function to allow additional time for DNA repair after damage is incurred, however, genetic studies in yeast suggest that components of the checkpoint pathway may also be involved in DNA lesion processing (Lydall and Weinert, 1995). Recent evidence suggests that this may also be the case for p53, as suggested by numerous reports linking p53 function to DNA repair. Thus, loss of p53 function might contribute to genomic instability independent of G1-arrest. In the present study, we explored the effect of p53 disruption and consequences of antisense GADD45 expression on the DNA repair capacity of human colon carcinoma RKO cells. DNA repair was assayed using host-cell reactivation of u.v.-damaged reporter plasmids and unscheduled DNA synthesis experiments in transiently-transfected cells. We show that a number of transfected genes that suppress p53 function reduce the ability of cells to repair u.v.-induced DNA damage. Moreover, cells in which expression of the p53-regulated gene GADD45 was blocked by antisense vectors, also showed altered levels of DNA repair. Blocking Gadd45 expression by constitutive antisense expression sensitized cells to killing by u.v.-radiation or by cis-platinum (II) diamine-dichloride (CDDP, or cisplatin), a cancer chemotherapy drug which produces DNA cross-links. These findings suggest the involvement of downstream effectors of the p53 pathway in the coordination of cell cycle arrest and DNA repair.

Antineoplastic Agents↗
PubMed2004

Aprataxin, a novel protein that protects against genotoxic stress.

Ataxia-oculomotor apraxia (AOA1) is a neurological disorder with symptoms that overlap those of ataxia-telangiectasia, a syndrome characterized by abnormal responses to double-strand DNA breaks and genome instability. The gene mutated in AOA1, APTX, is predicted to code for a protein called aprataxin that contains domains of homology with proteins involved in DNA damage signalling and repair. We demonstrate that aprataxin is a nuclear protein, present in both the nucleoplasm and the nucleolus. Mutations in the APTX gene destabilize the aprataxin protein, and fusion constructs of enhanced green fluorescent protein and aprataxin, representing deletions of putative functional domains, generate highly unstable products. Cells from AOA1 patients are characterized by enhanced sensitivity to agents that cause single-strand breaks in DNA but there is no evidence for a gross defect in single-strand break repair. Sensitivity to hydrogen peroxide and the resulting genome instability are corrected by transfection with full-length aprataxin cDNA. We also demonstrate that aprataxin interacts with the repair proteins XRCC1, PARP-1 and p53 and that it co-localizes with XRCC1 along charged particle tracks on chromatin. These results demonstrate that aprataxin influences the cellular response to genotoxic stress very likely by its capacity to interact with a number of proteins involved in DNA repair.

Apraxias↗
PubMed2001

Genetic heterogeneity and alterations in chromosome 9 loci in a localized region of a functional pituitary adenoma.

The molecular alterations reported in pituitary adenomas include mutations at the G(s)alpha in somatotrophinomas, and hypermethylation of the p16 tumor suppressor gene. There are, however, no reports of genomic instability or intratumor genetic heterogeneity in pituitary adenomas. We have studied the microsatellite loci on the short arm of chromosome 9 (9p) and the DNA fingerprinting pattern, of adjacent compartments, about 2 mm across, in a functional chromophobe pituitary adenoma secreting growth hormone and prolactin. The microsatellite loci were studied by PCR amplification using locus specific primers, while the DNA fingerprinting pattern was studied by randomly amplified polymorphic DNA (RAPD) analysis. Normal leukocyte DNA was taken as control. Only one compartment (Ta) showed alterations in several of the microsatellite loci and in the RAPD pattern vis a vis corresponding normal DNA and also the other two compartments of the tumor. This provides evidence for the localized nature of genomic instability in this tumor.

Adenoma↗
PubMed1997

Allelotype and replication error phenotype of small cell lung carcinoma.

Allelotype and replication error (RER) phenotype analyses were performed to clarify the pathogenetic significance of inactivation of tumor suppressor genes and genomic instability in the genesis and progression of small cell lung carcinoma (SCLC). We examined 37 cases of SCLC for loss of heterozygosity (LOH) and microsatellite instability at 49 loci on all 39 nonacrocentric chromosomal arms. LOH was frequently (>70%) detected on chromosomes 3p (29/32, 90.6%), 5q (15/21, 71.4%), 13q (25/26, 96.2%), 17p (22/25, 88.0%), and 22q (24/33, 72.7%). Frequent LOH (>70%) on these loci was observed even among seven cases of stage I tumors. The incidence of LOH on all 39 nonacrocentric chromosomal arms was not significantly different between primary tumors and metastases. These results suggest that inactivation of multiple tumor suppressor genes accumulates relatively early during progression of SCLC and it may be responsible for clinically and biologically aggressive phenotype of SCLC. RER was observed in 6/37 (16.2%) of SCLC, however, RER at multiple loci was observed only in two cases. Therefore, it was indicated that genomic instability is uncommon, but might play a role in the genesis of a small subset of SCLC.

Alleles↗
PubMed2004

Increased level of oxidative stress in genomically unstable cell clones.

Recently, we reported that ultraviolet radiation induces delayed mutations in mammalian cells. At the same level of cell death the oxidative component of sunlight (ultraviolet A radiation) was as potent in inducing this kind of genomic instability as ultraviolet B radiation. Ultraviolet B radiation predominantly harms cells by direct damage to DNA and thus is much more mutagenic than ultraviolet A radiation. From that study, clones with a significantly increased mutation rate in the hypoxanthine phosphoribosyl transferase gene were obtained. These genomically unstable clones were also found to have a higher variance in the number of chromosomes than the unirradiated control cells, indicating chromosomal instability. The mechanisms for induction and maintenance of radiation induced genomic instability are not known, but some studies suggest that reactive oxygen species might be involved. In the present study, we have measured the level of potentially mutagenic peroxides in the genomically unstable clones. The levels of intracellular peroxides and lipid peroxides were measured using the probes dihydrorhodamine 123 and diphenyl-1-pyrenyl-phosphine, respectively. The unstable clones had elevated levels of oxidants, supporting the hypothesis that intermediate reactive oxygen species might have a role in the maintenance of genomic instability induced by ultraviolet radiation.

Animals↗
PubMed2026

Integrated transcriptomic and immunogenomic analysis unravels the immunological functions and prognostic landscape of WD repeat domain 76.

BackgroundWD Repeat Domain 76 (WDR76) plays a potential role in cellular regulation; however, its comprehensive landscape across human malignancies and its specific biological function in hepatocellular carcinoma (HCC) remain largely unexplored.MethodsWe conducted a systematic pan-cancer analysis utilizing multi-omics data from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Line Encyclopedia (CCLE) atabases to evaluate WDR76 expression, subcellular localization, and its correlation with clinicopathologic features, genomic instability, and immune infiltration. Diagnostic and prognostic values were assessed via Receiver operating characteristic (ROC) and Kaplan-Meier analyses. Furthermore, the functional role of WDR76 in HCC was validated in vitro using Hep-3B and Huh7 cell lines through siRNA-mediated knockdown, followed by CCK-8, wound-healing, and transwell assays.ResultsWDR76 was significantly upregulated in the majority of tumor types, including LIHC, LUAD, and COAD, while exhibiting nuclear localization. Elevated WDR76 expression correlated with advanced tumor staging, metastasis, and poor clinical outcomes across multiple cohorts, particularly in ACC, KIRP, and LIHC. ROC analysis highlighted its exceptional diagnostic precision in cancers such as GBM and LIHC. Immunologically, WDR76 expression was intricately linked to immune cell infiltration, immune checkpoint markers, and genomic instability parameters, suggesting a role in shaping the tumor microenvironment. Drug sensitivity profiling revealed that high WDR76 levels correlate with resistance to specific chemotherapeutic agents. Experimentally, silencing WDR76 in HCC cells significantly suppressed cell proliferation, migration, and invasion capabilities.ConclusionOur study establishes WDR76 as a robust pan-cancer prognostic biomarker and a potential immunotherapeutic target. Specifically, we provide experimental evidence that WDR76 functions as an oncogenic driver in liver cancer, promoting malignant phenotypes and offering a novel avenue for targeted therapeutic intervention.

Humans↗
PubMed1995

Cell cycle regulation in response to DNA damage in mammalian cells: a historical perspective.

Cell cycle delay has long been known to occur in mammalian cells after exposure to DNA-damaging agents. It has been hypothesized that the function of this delay is to provide additional time for repair of DNA before the cell enters critical periods of the cell cycle, such as DNA synthesis in S phase or chromosome condensation in G2 phase. Recent evidence that p53 protein is involved in the delay in G1 in response to ionizing radiation has heightened interest in the importance of cell cycle delay, because mutations in p53 are commonly found in human cancer cells. Because mammalian cells defective in p53 protein show increased genomic instability, it is tempting to speculate that the instability is due to increased chromosome damage resulting from the lack of a G1 delay. Although this appears at first glance to be a highly plausible explanation, a review of the research performed on cell cycle regulation and DNA damage in mammalian cells provides little evidence to support this hypothesis. Studies involving cells treated with caffeine, cells from humans with the genetic disease ataxia telangiectasia, and cells that are deficient in p53 show no correlation between G1 delay and increased cell killing or chromosome damage in response to ionizing radiation. Instead, G1 delay appears to be only one aspect of a complex cellular response to DNA damage that also includes delays in S phase and G2 phase, apoptosis and chromosome repair. The exact mechanism of the genomic instability associated with p53, and its relationship to the failure to repair DNA before progression through the cell cycle, remains to be determined.

Animals↗
PubMed1994

Determination of a putative recombinogenic human hepatitis B virus sequence and its binding cellular protein.

Previously, we reported that C4BglII196, a 196-base pair subgenomic fragment of hepatitis B virus (HBV) covering its precore region, enhances in vitro recombination in the presence of extracts from actively dividing cells (Hino, O., et al. Proc. Natl. Acad. Sci. USA, 88:9248-9252, 1991). The results indicated that HBV may play some role in causing genomic instability during chronic hepatitis. In the present study, we showed that 15AB, a 60-base pair subgenomic fragment of HBV DNA (nucleotides 1855-1914) within C4BglII196 is indispensable for enhancement of in vitro recombination, using the mouse leukemia cell 70Z/3, as the cellular extract source. 15AB, thought to be the encapsidation signal of HBV pregenomic RNA and U5-like retrovirus long terminal repeat, was found to bind specifically to an approximately 100 kDa protein of 70Z/3 by southwestern blotting. Production of a mutation in the 15AB region decreased both its binding activity to 100 kDa protein and the in vitro recombination activity. Our present results thus suggest that 15AB might be a recombinogenic sequence and the 100-kDa protein may be a putative recombinogenic protein in eukaryotes, triggering genomic instability and facilitating carcinogenesis.

Base Sequence↗
PubMed1998

Genomic fluidity is a necessary event preceding the acquisition of tumorigenicity during spontaneous neoplastic transformation of WB-F344 rat liver epithelial cells.

The genomic evolution of a cohort of WB-F344 rat liver epithelial cell lineages undergoing spontaneous neoplastic transformation was followed to define the mechanistic relationship between genomic instability and progression to the neoplastic phenotype. Eighteen independent populations of WB-F344 cells (initiated from a single diploid-founding population) were subjected to 12 cycles of selective growth at confluent cell density, and cellular DNA contents were measured after each selection cycle. Flow cytometry demonstrated significant gains in the amount of G1 DNA after selection cycles 3, 6, and 7 in 44% (8 of 18), 89% (16 of 18), and 39% (7 of 18) of the cell populations, respectively. All populations subsequently lost DNA and returned to a diploid or pseudo-diploid DNA content within 1 to 2 selection cycles after the appearance of an increased DNA content. Additionally, appearance and subsequent disappearance of aneuploid or tetraploid subpopulations was observed in 11% (2 of 18) and 83% (15 of 18) of the experimental lineages, respectively. Although perturbations of G1 DNA content were apparent as early as selection cycle 3, at least 8 cycles of selective growth were required for the acquisition of tumorigenicity. While the independent lineages demonstrated significant fluctuations in G1 DNA content between selection cycles 3 and 8, the majority (11 of 13) of the populations contained a diploid or pseudo-diploid DNA content at the time tumorigenicity was expressed. Genomic instability preceded the acquisition of tumorigenic potential in rat liver epithelial cells subjected to selective growth conditions of maintenance at confluence, and may be required for its expression.

Aneuploidy↗
PubMed2006

Deregulated cyclin E promotes p53 loss of heterozygosity and tumorigenesis in the mouse mammary gland.

Deregulation of cyclin E expression and/or high levels have been reported in a variety of tumors and have been used as indicators of poor prognosis. Although the role that cyclin E plays in tumorigenesis remains unclear, there is evidence that it confers genomic instability when deregulated in cultured cells. Here we show that deregulated expression of a hyperstable allele of cyclin E in mice heterozygous for p53 synergistically increases mammary tumorigenesis more than that in mice carrying either of these markers individually. Most tumors and tumor-derived cell lines demonstrated loss of p53 heterozygosity. Furthermore, this tumor susceptibility is related to the number of times the transgene is induced indicating that it is directly attributable to the expression of the cyclin E transgene. An indirect assay indicates that loss of p53 function is an early event occurring in the mammary epithelia of midlactation mammary glands in which cyclin E is deregulated long before evidence of malignancy. These data support the hypothesis that deregulated expression of cyclin E stimulates p53 loss of heterozygosity by promoting genomic instability and provides specific evidence for this in vivo. Cyclin E deregulation and p53 loss are characteristics often observed in human breast carcinoma.

Animals↗
PubMed2006

Mobilization of RAG-generated signal ends by transposition and insertion in vivo.

In addition to their essential roles in V(D)J recombination, the RAG proteins have been found to catalyze transposition in vitro, but it has been difficult to demonstrate transposition by the RAG proteins in vivo in vertebrate cells. As genomic instability and chromosomal translocations are common outcomes of transposition in other species, it is critical to understand if the RAG proteins behave as a transposase in vertebrate cells. To facilitate this, we have developed an episome-based assay to detect products of RAG-mediated transposition in the human embryonic kidney cell line 293T. Transposition events into the target episome, accompanied by characteristic target site duplications, were detected at a low frequency using RAG1 and either truncated "core" RAG2 or full-length RAG2. More frequently, insertion of the RAG-generated signal end fragment into the target was accompanied by deletions or more complex rearrangements, and our data indicate that these events occur by a mechanism that is distinct from transposition. An assay to detect transposition from an episome into the human genome failed to detect bona fide transposition events but instead yielded chromosome deletion and translocation events involving the signal end fragment mobilized by the RAG proteins. These assays provide a means of assessing RAG-mediated transposition in vivo, and our findings provide insight into the potential for the products of RAG-mediated DNA cleavage to cause genome instability.

Base Sequence↗
PubMed2003

The yeast Sgs1 helicase is differentially required for genomic and ribosomal DNA replication.

The members of the RecQ family of DNA helicases play conserved roles in the preservation of genome integrity. RecQ helicases are implicated in Bloom and Werner syndromes, which are associated with genomic instability and predisposition to cancers. The human BLM and WRN helicases are required for normal S phase progression. In contrast, Saccharomyces cerevisiae cells deleted for SGS1 grow with wild-type kinetics. To investigate the role of Sgs1p in DNA replication, we have monitored S phase progression in sgs1Delta cells. Unexpectedly, we find that these cells progress faster through S phase than their wild-type counterparts. Using bromodeoxyuridine incorporation and DNA combing, we show that replication forks are moving more rapidly in the absence of the Sgs1 helicase. However, completion of DNA replication is strongly retarded at the rDNA array of sgs1Delta cells, presumably because of their inability to prevent recombination at stalled forks, which are very abundant at this locus. These data suggest that Sgs1p is not required for processive DNA synthesis but prevents genomic instability by coordinating replication and recombination events during S phase.

Bromodeoxyuridine↗
PubMed2003

The p53 tumor suppressor gene and nuclear protein: basic science review and relevance in the management of bladder cancer.

PURPOSE: An extensive body of literature regarding p53 has accumulated during the last 2 decades. The cellular mechanisms of p53 are complex yet well-defined, whereas its clinical usefulness in the management of bladder cancer remains controversial. We outline the basic constitutive functions of p53 and summarize its current role in the management of transitional cell carcinoma of the bladder. MATERIALS AND METHODS: We conducted a MEDLINE based literature review concerning the fundamental mechanisms of p53 and its role in the management of bladder cancer. RESULTS: The p53 gene is a tumor suppressor gene that acts as "guardian of the genome." Many diverse cellular events, including DNA damage and hypoxia, activate the p53 gene. The p53 protein functions as a transcription factor, regulating downstream genes involved in cell cycle arrest, DNA repair and programmed cell death. Loss of p53 function confers genomic instability, impaired apoptosis and diminished cell cycle restraint. Therefore, p53 mutations select for certain critical features of malignancy. Alteration of P53 is the most common mutation in human cancer. Roughly half of all human malignancies, including many urological cancers, exhibit p53 mutations. In bladder cancer p53 mutations have been associated with higher tumor grade and advanced stage, as well as progression of superficial disease to muscle invasion. Moreover, p53 nuclear over expression appears to be an independent predictor of disease progression and decreased survival after cystectomy. CONCLUSIONS: The importance of p53 mutation in tumor cell biology is irrefutable. Wild-type p53 mediates imperative functions such as regulation of the cell cycle and programmed cell death. Deficiency of p53 function by mutation or inactivation abrogates normal cell cycle checkpoints and apoptosis, generating a favorable milieu for genomic instability and carcinogenesis. However, despite the manifest importance of p53 in human malignancy, its current role in the management of bladder cancer appears somewhat limited. A multitude of retrospective studies have associated p53 mutations with adverse outcomes in superficial and muscle invasive disease. Nonetheless, randomized prospective studies are needed to determine the potential clinical implications of p53 in bladder cancer.

Animals↗
PubMed1999

Micronuclei formation and aneuploidy induced by Vpr, an accessory gene of human immunodeficiency virus type 1.

Vpr, an accessory gene of HIV-1, induces cell cycle abnormality with accumulation at G2/M phase and increased ploidy. Since abnormality of mitotic checkpoint control provides a molecular basis of genomic instability, we studied the effects of Vpr on genetic integrity using a stable clone, named MIT-23, in which Vpr expression is controlled by the tetracycline-responsive promoter. Treatment of MIT-23 cells with doxycycline (DOX) induced Vpr expression with a giant multinuclear cell formation. Increased micronuclei (MIN) formation was also detected in these cells. Abolishment of Vpr expression by DOX removal induced numerous asynchronous cytokinesis in the multinuclear cells with leaving MIN in cytoplasm, suggesting that the transient Vpr expression could cause genetic unbalance. Consistent with this expectation, MIT-23 cells, originally pseudodiploid cells, became aneuploid after repeated expression of Vpr. Experiments using deletion mutants of Vpr revealed that the domain inducing MIN formation as well as multinucleation was located in the carboxy-terminal region of Vpr protein. These results suggest that Vpr induces genomic instability, implicating the possible role in the development of AIDS-related malignancies.

Acquired Immunodeficiency Syndrome↗
PubMed2006

A simple model system for age-dependent DNA damage and cancer.

Aging is the major risk factor for many human cancers. However, the mechanisms responsible for the effect of aging on tumor incidence are poorly understood, in part because few model systems are available to study age-dependent genomic instability. Furthermore, the role of DNA mutations in "normal aging" and "life span extension" is unclear. Our laboratory has developed a novel method to study aging in yeast based on the survival of non-dividing populations (chronological life span). Two major pathways have been identified that control chronological aging: the Ras/PKA/Msn2/4 and the Sch9 pathways. The downregulation of either of them promotes life span extension. Importantly, similar pathways (insulin/IGF-I-like), regulate longevity in higher eukaryotes suggesting a common evolutionary origin for the life span-regulatory mechanisms. Moreover, both Ras and Sch9 are functional homologs of two major mammalian oncogenes (Ras and Akt), which underlines the close link between cancer and aging. By combining chronological life span with simple assays for the detection of DNA mutations and dedifferentiation we have developed a powerful system to identify genes that regulate genomic instability and understand the fundamental mechanisms that may be responsible for age-dependent DNA mutations and cancer in mammals. Here, we describe the use of this system to monitor the age-dependent accumulation of different types of DNA mutations including base substitutions, frame-shift mutations, and gross chromosomal rearrangements (GCRs).

Aging↗