Deficiencies in DNA Damage Recognition and Repair in HGPS Cells:
Progeria causes chromatin perturbations, which result in the formation of DSBs (double-strand breaks) and abnormal DDR (DNA-damage response). Progerin may disrupt DDR pathways in HGPS cells. Progerin accumulation results in disruption of functions of some replication and repair factors, causing the mislocalization of XPA protein to the replication forks, replication fork stalling and, subsequently, DNA DSBs. The binding of XPA to the stalled forks excludes normal binding by repair proteins, leading to DSB accumulation, which actives ATM and ATR checkpoints, and arresting cell-cycle progression.
As mutant lamin proteins takeover the immune system, they sequester replication and repair factors, leading to "stalled replication forks, which collapse into DNA double-strand beaks (DSBs)." These DSBs bind to Xeroderma pigmentosum group A (XPA) protein, which replaces the usual binding by DNA DSB repair proteins. This compromised binding can signal activation of ATM and ATR, arresting cell cycle progression, contributing to arrested growth.
Rather than the recruitment of DSB repair proteins to DNA damage sites for repair as part of the damage response, nuclear foci of Rad50/Rad51 did no colocalize with the γ-H2AX foci in HGPS cells. Although all other elements of the damage response system such as the ATR and ATM checkpoints and Chk1 and Chk2, the critical components for repair of DNA DSBs and the resting of stalled replication forks, were not activated. Failure to recruit repair factors to DNA damage sites result in irreparable DNA damage in HGPS cells.
The binding of Xeroderma pigmentosum group A (XPA) protein to laminpathy-generated DSBs played a factor in the loss...
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... absence of insulin receptor gene rearrangement, which could account for the severe insulin resistance (ncbi.nlm.nih.gov).
Works Cited
Musich R. Phillp, & Zou Yue. (2009). Genomic Instability and DNA Damage Responses in Progeria Arising from Defective Maturation of Prelamin A. Impact Aging Papers.
Parreno, Justin, & Cruz V. Alyssa. (2011). Accelerated Aging in Patients with Hutchinson- Gilford Progeria Syndrome: Clinical SIgns, Molecular Causes, Treatments, and Insights into the Aging Process. UBCMJ.
Pollex RL, Hegele RA. (2004). Hutchinson-Gilford progeria syndrome. Clinical Genetics- Blackwell Munksgaard.
Sarkar K P, & Shinton A R. (2000). Hutchinson-Guilford progeria syndrome. Postgraduate Medical Journal.
Vignolo M., Gherzi R., Bellini C., & Briata P. (1991). Insulin receptor gene expression is reduced in cells from a progeric patient. Pub Med. Gov.
The beta cells affect a person’s glucose regulations within the blood. This is because the beta cells are in charge of sending insulin arou...
Rosenfeld, Louis. Insulin: Discovery and Controversy. 2002. American Association for Clinical Chemistry Inc. 9 October 2009 .
According WebMD 2014. Diabetes mellitus (or diabetes) is a chronic, lifelong condition that affects your body's ability to use the energy found in food. There are three major types of diabetes. Type 1 diabetes mellitus, type 2 diabetes mellitus and gestational diabetes. It is a hormonal disorder of the pancreas either decrease in insulin level also known as hypoinsulinism or increase in insulin level also known as hyperinsulinism. Lowered amounts, insufficient of, or ineffective use of insulin leads to the disorder of diabetes mellitus. It is common chronic disease requiring lifelong behavioral and lifestyle changes. According to Peakman (2012). The development of type 1 diabetes mellitus is a genetic and an autoimmune process that results in destruction of the beta cells of the pancreas, leading to absolute insulin deficiency. There is usually a pre-diabetic phase where autoimmunity has already developed but with no clinically apparent insulin dependency. Insulin autoantibodies can be detected in genetically predisposed individuals as early as 6-12 months of age. In persons genetically susceptible to type 1 diabetes, a triggering event, possibly a viral infection the leads to production of autoantibodies that kill the beta cells and results in decline and a lack of insulin secretion. According to Wherrett. It is caused by impaired insulin secretion and insulin resistance and has a gradual onset. Those with type 2 diabetes may eventually need insulin treatment. Gestational diabetes mellitus is glucose intolerance during pregnancy in a woman not previously diagnosed with diabetes, this may occur if placental hormones counteract insulin, causing insulin intolerance. Complications in diabetes mellitus includes: Hypoglycemia it is ca...
According to Lewis and associates, DM is a chronic disease that affects multiple body systems. For the purpose of this paper, only DM type 2 will be discussed based on the assumption that a majority of patients aged 60 years or older have this type. The primary defects of this disease consist of insulin resistance, decreased insulin production, inappropriate glucose production by the liver, and alterations in production of adipokines. Insulin resistance is the result of defects in the body’s insulin receptors. This finding predates all cases of DM type 2 and the development of impaired glucose tolerance. In insulin resistance, beta cells in the pancreas are stimulated to increase insulin production to compensate for the lack of response by the insulin receptors. Gradually, the beta cells begin to fail to secrete enough insulin to meet the body’s demands resulting in hyperglycemia. As a result of increased glucose in the liver, the liver begins to malfunction and release glucose at inappropriate times, thereby worsening hyperglycemia. Adding to the problem, glucose and fat metabolism is altered in adipose tissue, which is generally abundant in those with DM type 2. (Lewis et al., 2011)
The faulty responsiveness of body tissues to insulin normally entails the insulin receptor found in cell membranes. The other type, the gestational diabetes happens in women who have not been diagnosed with diabetes before and show elevated blood glucose amounts during pregnancy. There is no explicit reason that has been acknowledged but it is assumed that the hormones secreted dur...
Insulin resistance can be defined as a physiological condition in which cells have a diminished response to normal actions of the hormone insulin. Insulin is produced, but the cells become resistant and are less capable of transporting glucose from the bloodstream to muscle and other tissues. In horses, insulin resistance is associated with a number of diseases such as Equine Metabolic Syndrome (Powell, et al., 2002; Hoffman, et al., 2003;Vick, et al., 2006 and Frank, et al., 2009), Equine Cushing Disease (McGowan, et al., 2004 and Walsh, et al., 2009) and Laminitis (Treiber, et al., 2006;Bailey, et al., 2007;M Obesity and insulin resistance in ponies has become a common problem and there is a growing awareness of the role that diet and exercise have to play (Jeffcott, et al., 1986; Frank, et al., 2006 and Vick & Adams, 2007). Over-expressed adipocytokines, such as leptin, have been suggested to impair insulin signalling and cause the up regulation of inflammatory cytokines.
Schulman, Joshua M., and David E. Fisher. "Abstract." National Center for Biotechnology Information. U.S. National Library of Medicine, 28 Aug. 0005. Web. 24 Apr. 2014.
Precise chromosomal DNA replication during S phase of the cell cycle is a crucial factor in the proper maintenance of the genome from generation to generation. The current “once-per-cell-cycle” model of eukaryotic chromosome duplication describes a highly coordinated process by which temporally regulated replicon clusters are sequentially activated and subsequently united to form two semi-conserved copies of the genome. Replicon clusters, or replication domains, are comprised of individual replication units that are synchronously activated at predetermined points during S phase. Bi-directional replication within each replicon is initiated at periodic AT-rich origins along each chromosome. Origins are not characterized by any specific nucleotide sequence, but rather the spatial arrangement of origin replication complexes (ORCs). Given the duration of the S phase and replication fork rate, adjacent origins must be appropriately spaced to ensure the complete replication of each replicon. Chromatin arrangement by the nuclear matrix may be the underpinning factor responsible for ORC positioning. The six subunit ORC binds to origins of replication in an ATP-dependent manner during late telophase and early G1. In yeast, each replication domain simply contains a single ORC binding site. However, more complex origins are characterized by an initiation zone where DNA synthesis may begin at numerous locations. A single round of DNA synthesis at each activated origin is achieved by “lic...
Metabolic Syndrome (syndrome X, insulin resistance syndrome) is the name for a group of risk factors that raise your risk for diabetes mellitus (DM), cardiovascular disease (CVD), and other health problems, such as diabetes and stroke.2 It is characterized by abdominal obesity, insulin resistance, hypertension, low HDL, and elevated triglycerides. Some hallmarks of metabolic syndromes are dyslipidemia, central adiposity, and a predisposition to atherosclerotic cardiovascular disease, certain cancers, hypertension, and type 2 diabetes mellitus. Genetics appears to play an important role in predisposing certain individuals and populations to the development of metabolic syndrome.1 Multiple environmental factors modify this genetic predisposition and include physical inactivity, advancing age, cigarette smoking, and endocrine dysfunction. The presence of one or either of these signs should alert the clinician to search for other biochemical abnormalities that may be associated with the metabolic syndrome.
2. Type 2 on the other hand, results from the cell’s inability to use insulin appropriately (RCT).
Type 1 diabetes has a genetic onset that often occurs in adolescence (Porth, 2005). It is an autoimmune disease in which the insulin-producing beta cells within the liver are destroyed (Dorman, 1993). This causes a deficiency in insulin secretion, which ultimately leads to high blood glucose levels, also referred to as hyperglycemia (Guthrie & Guthrie, 2004). The mechanism for insulin deficiency leading to hyperglycemia is described in more detail in the following section and in Figure 1.
When you have gestational diabetes, either your body does not make enough insulin during your pregnancy or your cells are unable to use the insulin in the way that they need.... ... middle of paper ... ... Baby Center. (2011).
Diabetes is a chronic disorder of metabolism characterized by a partial or complete deficiency of the hormone insulin. With this, there are metabolic adjustments that occur everywhere in the body. Specific to this child is Type One Diabetes. This is characterized by demolition of the pancreatic beta cells, which produce insulin. Because of this, it leads to complete insulin deficiency. Within Type One diabetes, there are two different forms. First there is immune-mediated deficiency, which typically results from an autoimmune destruction of the beta cells. The second type is called idiopathic type one, in which the cause is unknown. (Wong, Hockenberry, Wilson, 2015)
Throughout the whole of the United Kingdom, between 2 and 3 of every 100 people have a known form of diabetes (DTC, 2004). What is diabetes? Explained simply, it is a disease in which the body does not produce or properly use insulin. In the normal state of glucose function, there is a stable release and uptake of glucose, regulated by two hormones produced in the pancreas, glucagon and insulin. There are two distinct mechanisms which give rise to the abnormal blood glucose levels seen in patients with type I and type II diabetes. In type I diabetes, a deficiency in insulin production at the pancreas results in elevated blood glucose levels due to the lack of hormonal regulation. In type II diabetes, although the pancreas produces regular levels of insulin, the body resists the effect of insulin, inhibiting the ability of insulin to break down glucose in the blood. Because of the inherent differences in the biochemical mechanisms of these two diseases, the characteristics associated with type I and type II diabetes are very different. The typical onset of type I diabetes is usually ...
Insulin is a hormone used to control blood glucose. This hormone can act on cells to: stimulate glucose, protein, and lipid metabolism. Understanding insulin is important for knowing its effect if there is an inadequate amount in the body. Before scientists understood insulin, people who’s bodies stopped producing the hormone