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article we are editing -> Molecular lesion

Background
Although cells contain many proofreading and repair systems for DNA, the body receives approximately tens of thousands of DNA lesions per day. DNA lesions, by definition, are any change in the double strand’s nucleotide sequence that leads to a change in structure or information .The kind of damage associated with a DNA lesion varies from mismatching of the base pairs, to single-stranded breaks, to abasic sites -- all of which can lead to transcription (link to article on transcription) disruption and genome replication problems. These issues may then lead to small mutations or life- threatening abnormalities.

Damage
DNA damage can be caused by an innumerable amount of different events, some of the most common being depurination, lesions caused by oxygen-reactive agents, cytosine deamination, and the tautomerization of DNA bases. Oxygen-reactive agents are produced as byproducts from redox reactions within the body or by lymphocytes after digesting a foreign molecule. (add info about peroxides) When oxidized, guanine turns into 8-oxo-guanine, which causes dire damage within the mitochondria and is thought to be one of the reasons for the aging process. Cytosine deamination commonly occurs under physiological conditions and essentially is the deamination of cytosine. This process yields uracil as its product, which is not a base pair found within DNA. This process causes extensive DNA damage is the reason for why ancient DNA is difficult to analyze. Lastly, if tautomerization of DNA bases occurs during DNA replication, incorrect daughter strands of DNA may form, ultimately leading to point mutations.

The environment also contributes to many of the lesions seen within DNA. For example, UV light, a form of ionizing radiation, causes direct DNA damage by initiating a synthesis reaction between two thymine molecules. Carcinogens are known to cause a number of DNA lesions, such as single-strand breaks, double- strand breaks, and covalently bound chemical DNA adducts. The damage associated with covalent DNA adducts is now thought to be the “central dogma of chemical carcinogenesis”.


 * List out other common lesions: Single-stranded and double stranded breaks and their characteristics.

Repair

 * DNA damage responses (DDR)- detail what these are and what types of damage they fix
 * Mismatch repair and how it works
 * Base-excision repair- deamination of cytosine to uracil ( https://bio.libretexts.org/Bookshelves/Biochemistry/Book%3A_Biochemistry_Free_and_Easy_(Ahern_and_Rajagopal)/05%3A_Flow_of_Genetic_Information/5.02%3A_DNA_Repair)
 * Single stranded base repair
 * Double stranded base repair
 * Nucleotide Excision Repair- UV damage ( https://bio.libretexts.org/Bookshelves/Biochemistry/Book%3A_Biochemistry_Free_and_Easy_(Ahern_and_Rajagopal)/05%3A_Flow_of_Genetic_Information/5.02%3A_DNA_Repair)

Disease Effects

 * Some lesions are not caught by the systems in place when the DNA is being replicated ( https://www.nature.com/articles/1206006 )
 * DNA polymerases can’t copy DNA past the lesion area
 * Cells have specialized DNA polymerases that help with a process called Translesion Synthesis, which allows for DNA to be copied past the problem areas. There’s a huge risk associated with generating mutations at a high frequency.

-  ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2906700/ )

-  Cancer- Which lesions are associated with it as well as how carcinogens exacerbate lesions

- Neurodegenerative disorders-- Alzheimers, Huntington’s, and Parkinson’s

- Other heritable diseases (fragile X, Diabetes, Huntington’s, mitochondrial issues)

- Immune deficiencies - B and T cell immune problems

- aging, cardiovascular disease

Background
In the cell, RNA is essential for gene expression, regulation, and blah blah blah. Similarly to DNA, it is subject to damage caused by endogenous or exogenous factors. It has been found in humans that base lesions are more abundant in RNA that in DNA. Oxidative base changes and oxidatively induced strand breaks are a few of the well-characterized RNA lesion types. RNA may be more prone to oxidation compared to DNA due to its proximity to the electron transport chain.

Damage
RNA bases are mainly oxidized by reactive oxygen species (ROS) and reactive nitrogen species (RNS) involved in the electron transport chain and 5-lipoxygenases. Exogenous factors such as tobacco use, other drugs, and ionizing radiation can result in RNA base lesions. An oxidized RNA base will either lead to strand breaks or an oxidatively modified base. The primary ROS responsible for direct oxidation of nucleobases are the hydroxyl radical and singlet oxygen. The few oxidative lesions which have been characterized so far are 5-hydroxyuridine (5-HO-rU), 5-hydroxycytidine (5-HO-rC), 8-oxo-7,8-dihydroguanosine (8-oxo-rG), and 8-oxo-7,8-dihydroadenosine (8-oxo-rA).

RNA oxidation has direct consequences in translation. mRNA affected by oxidative lesions is still recognized by ribosome, but the ribosome will undergo stalling and dysfunction. This results in proteins will either having decreased expression or truncation. These can lead to aggregation and general dysfunction. One study synthetically incorporated oxidized bases into RNA, showing that oxidated nucleobases can change base pairing preferences, therefore affecting protein readout.

Repair
There are very few reports on interventions that repair or reduce RNA oxidation. The fate of oxidized RNA is largely unexplored, but the major mechanisms seem to be RNA degradation and elimination. One the first reported RNA repair mechanisms


 * There are very few reports on interventions that reduce RNA oxidation (6)
 * Fate of oxidized RNA is largely unknown(1)
 * Major mechanisms seem to be degradation and elimination
 * RNA is typically in an intramolecularly bound state (3)
 * First reported example of an RNA repair mechanism was rejoining cleaved RNA by T4 ligase (5)
 * This would account for base pair breaks, but not single base pair oxidation that does not result in strand breaks
 * Apurinic endonuclease plays a role in rRNA quality control and may repair oxidized RNA (5)
 * There are also measures in the cell which prevent oxidized bases in the nucleotide pool from being incorporated (5)

Disease Effects

 * Linked to aging and other neurodegenerative diseases (1)
 * RNA oxidation is an early event in these rather than a byproduct (alzheimers)
 * Type 2 diabetes
 * 8-oxo-guanosine is predictive of death if excreted by patient (5)
 * ALS (5)
 * Some RNA species are particularly susceptible to damage
 * Disturbances noted in the ETC, CAC, protein folding, etc.
 * Parkinson's
 * Down syndrome



Enzymes
Molecular lesions of enzymes are usually they are caused by mutations that end up destroying the enzyme's original function. This damage can be can be inherited, random, or caused by oxidative stress on the gene. Due to this, any enzyme function can possibly be reduced due to molecular lesions, and many disorders can arise.

Disease Effects
There are many different types of diseases caused by enzyme molecular lesions, however the most famously known is Schindler’s disease is a molecular lesion in the alpha-N-acetylgalactosaminidase gene that causes a is a devastating disease known as infantile neuroaxonal dystrophy. Symptoms include increased tissue accumulation, increased urinary output of glycopeptides and oligosaccharides. Decreased development may occur, and later on in life neurological regression becomes prominent. Additionally, inherited phosphofructokinase deficiency has been associated with the molecular lesions of the phosphofructokinase gene, and typically presents itself with anemia that may require medical intervention. However, this condition can also present itself on a spectrum, and may cause no symptoms other than hemolysis. Maltase deficiency/Glycogen Storage Disease Type II is also associated with molecular lesions. The molecular lesion of Maltase, an enzyme important in metabolism, has a genotype-phenotype correlation with the onset of symptoms. Age of onset is typically found later in adulthood in heterogeneous persons, however the condition is genetic and has been found clinically. This condition results in the decrease of β‐glucosidase activity, and once this pathway has been affected, it presents itself as the degradation of muscle fibers that progresses of muscle weakness or failure overtime.

Repair
There is no real treatment for diseases caused by molecular lesions on enzymes. Symptoms associated with these conditions are not necessarily problematic depending on the severity of the lesion. In some cases, blood transfusions, enzyme replacement therapy, or bone marrow transplants are necessary in order to prevent further damage.

History of Carbohydrate Molecular Lesions

 * Common types of carbohydrates that can be damaged:
 * Formation of the structural framework of RNA and DNA (ribonucleic acid and deoxyribonucleic acid).
 * structural elements in the cell walls of bacteria (peptidoglycan or murein), plants (cellulose) and animals (chitin).
 * linked to many proteins (glycoproteins) and lipids. Such linked carbohydrates are important in cell-cell communication and in interactions between cells and other elements in the cellular environment.
 * As "food" for energy supply (starch, glycogen, dextrans) and production of fats.
 * Specific carbohydrate-binding proteins in plants and animals are lectins, which are the partners that bind carbohydrate structures and facilitate cell-cell interaction.
 * Other types: malectin, selectin
 * ( https://www.eufic.org/en/whats-in-food/article/the-basics-carbohydrates )
 * ( https://courses.lumenlearning.com/wm-biology1/chapter/reading-types-of-carbohydrates/ )
 * ( https://en.wikibooks.org/wiki/Structural_Biochemistry/Carbohydrates )

Damage

 * Cellulose ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894906/ )
 * Altered cellulose synthesis affects the physical and structural properties of the cell wall. Plant cells can sense the changes in the wall through cell wall integrity sensing mechanisms (Wolf et al., 2012). For example, deficiency in cellulose synthesis in primary cesa mutants is often accompanied by excessive deposition of lignin in non-lignified cells (Cano-Delgado et al., 2003; Hematy et al., 2007). Excessive lignification is also seen in etl1 (At1g05850), a non-CESA mutant with defects in cellulose synthesis (Zhong et al., 2002). Although the molecular mechanism by which a reduction in cellulose biosynthesis triggers the lignification is unknown, it has been speculated that it is part of a response to cell wall damage. Consistent with the cell wall damage hypothesis, lesions in primary CESAs induced accumulation of jasmonic acid and ethylene, two plant hormones that have a major role in plant defense, indicating that cellulose deficiency mimics the effect of physical damage or certain biotic stresses (Ellis et al., 2001; Ellis et al., 2002; Cano-Delgado et al., 2003).
 * Lesions in KORRIGAN1 (KOR1) resulted in defects in cellulose synthesis in both primary and secondary cell walls, including defects in cytokinesis and unrestricted cell proliferation, root radial swelling, dwarfism and collapsed xylem (Nicol et al., 1998; Zuo et al., 2000; Lane et al., 2001 ; Sato et al., 2001 ; Szyjanowicz et al., 2004; Paredez etal., 2008). KOR1 encodes a putative membrane bound β-1,4 endoglucanase (Nicol et al., 1998; Rudsander et al., 2008; Liebminger et al., 2013).


 * Lectin : Changes to lectin binding during storage of RBCs suggest that significant changes occur to the carbohydrate structures at the RBC membrane. These findings provide further insight into the mechanisms of the RBC storage lesion and potential influence on RBC survival after transfusion. Our findings reported here demonstrate that old RBCs have lower lectin binding than young RBCs, and significant changes occur to the membrane‐associated carbohydrates of RBCs during storage. Whether the changes to lectin binding are due to cleavage of carbohydrate residues or arise from conformational remodeling of membrane molecules due to the physical changes that occur to RBCs during storage,6 such as changes to shape and size, which could alter the accessibility of lectins to certain carbohydrates, remains to be conclusively determined. Our results suggest that the changes that occur to RBCs during storage may not be entirely the same as those related to aging of RBCs. Further studies are warranted to determine the significance of these findings with regard to in vivo posttransfusion efficacy and survival of stored RBCs.
 * https://onlinelibrary.wiley.com/doi/full/10.1111/j.1537-2995.2007.01230.x

Repair

 * Currently, there are no known repairs that target specific carbohydrate lesions.
 * However, there has been research on the development of protein serum-based cancer diagnostics that target glycoproteins. Similarly, the glycoprotein hormone erythropoietin, from the kidneys, has improved the treatment for anemia by stimulating an increase in red blood cells.

Disease Effects

 * Glycoproteins play several roles in terms of the medical world. Modified carbohydrates have the ability to interfere with the interactions between carbohydrates and proteins. This leads to the inhibition of the cell–cell recognition and adhesion that is a major factor contributing to cancerous growth.
 * Improper glycosylation of membrane proteins destabilizes potassium channels which degrades human tissue and causes muscular dystrophy.
 * https://apps-webofknowledge-com.proxy.lib.umich.edu/full_record.do?product=WOS&search_mode=GeneralSearch&qid=2&SID=6AT4BWT8eUshJSFOvdO&page=1&doc=6&cacheurlFromRightClick=no

Background of Lipid Molecular Lesions
Molecular lesions of lipids are not a common area of study with regards to lesions of the macromolecule itself; however, several genetic diseases leading to lysosomal hydrolase deficiencies manifest as abnormally metabolized and stored lipids. Clinically, this presents as several lipid storage disorders. These diseases are both plentiful and diverse, examples being, Gaucher disease, sphingomyelinase deficiency (also known as Niemann-Pick disease (NPD) types A and B, Fabry’s disease, fucosidosis, Schindler disease, Krabbe disease, Farber disease, and Wolman disease. The first of these diseases to be analyzed and described was Gaucher’s disease (1882), followed by Fabry disease (1898). Due to improper lysosomal lipid storage of these diseases, early organ failure and death are incredibly common.

Damage
The damage in human lipid storage primarily occurs during glycosphingolipid metabolism, with potential for error at each step of the pathway. These errors are genetically predetermined, and diagnosis typically involves analyzing enzymatic activities and characterizing the lipid products that are ultimately stored. Diagnosis can also be done by focusing on specific enzymatic activity in isolated leukocytes or cultured fibroblasts. Urine metabolite analysis for mucopolysaccharidoses may also be useful in guiding diagnosis.

Repair
Typically there is no specific treatment of any lipid storage disease and only symptoms can be alleviated, however once a lipid storage disease is properly diagnosed, recombinant enzyme replacement therapy (ERT) is a newer treatment that may be applied. ERT is currently available for the treatment of Gaucher’s disease, Fabry disease, and mucopolysaccharidosis type I (MPS I), however research is expanding it as a potential therapy for several other lipid storage disorders.

Disease Effects
Lipid Storage Disorders are inherited deficiencies of lysosomal hydrolase, leading to lysosomal accumulation of the enzyme's specific sphingolipid substrate. They are rare hereditary disorders of fat metabolism, characterized by accumulation of distinct lipids cerebrosides, gangliosides, sphingomyelins in different body parts. Below are details associated with four specific examples of lipid storage disorders - Gaucher's Disease, Niemann-Pick Disease, Tay-Sachs Disease, and Fabry's Disease.


 * Gaucher’s Disease
 * Cerebrosides accumulate in liver, spleen, bone marrow, and lymph nodes
 * Glucocerebrosidase is defective
 * Lipid excess interferes with cell function, ultimately presenting as one of two clinical presentations
 * Infantile cerebral form where the child appears normal when born yet develops to become “apathetic and retarded,” eventually experiencing extreme nervous system symptoms and dying during the first year of life (this is more acute)
 * A form that presents at any age, associated with spleen enlargement, anemia, and patchy brown skin pigmentation (this is more chronic); the bones eventually change formation due to calcification errors, increasing likelihood of fractures and deformities
 * Niemann-Pick Disease
 * Associated with sphingomyelin deposition
 * Sphingomyelinase is defective
 * Shares many features of Gaucher’s disease, yet lipid deposition occurs in more areas of the body
 * Typically presents during the first year of life and death occurs prior to the age of four
 * Tay-Sachs Disease
 * Associated with ganglioside deposition
 * Also known as amaurotic (blind) idiocy
 * Gangliosides are deposited in central nervous system tissues, leading to the deterioration of the body tissues and causing extreme mental deficiency
 * Early symptoms include high noise sensitivity, muscle weakness, a cherry-red spot on the retina, and eventual vision loss which progresses towards blindness
 * Death usually occurs before the age of three
 * Fabry’s Disease
 * Associated with ceramide trihexoside deposition (related to sphingomyelins)
 * Ceramide trihexosidase is defective
 * Symptoms presented include purple skin elevations known as papules, heart enlargement, improper kidney function, cornea opacity, and blood vessel dilation
 * Sex-linked disease that mainly presents in males, often dying of kidney failure trained by cardiovascular disease