Methyl Mismatch Repair

Altered genes and uncontrolled growth may lead to tumors. These tumors can be benign (NOT cancerous) or malignant (cancerous). Benign tumors won’t spread but it can damage tissues around

On December 10, 2015, three profound individuals received the Nobel Prize in chemistry for their work on DNA repair systems. Paul Modrich, Thomas Lindahl, and Aziz Sancar studied how the cell repairs and protects the information held in its DNA; specifically, Paul Modrich focused on DNA mismatch repair. Since DNA constantly replicates, damage and incorrect pairings are expected, but enzymes watch over DNA as it replicates and repair any errors that occur. In the mismatch repair system, enzymes find the mismatch in the copy of DNA, cut the incorrect section out, and replace it with the correct sequence. Paul Modrich’s study of the mismatch repair system has provided the medical field with important information regarding cancer growth and the possibility of a cure.

Cancer is the development of faulty cells and is caused by mutations in the DNA of the cell which make it defective. Normal cells have methods to prevent cancer cells from forming, such as tumor suppressor genes but sometimes cancer can bypass these methods and grow out of control, forming tumors. If the cancer cells come into contact with the lymphatic system or circulatory system, it can travel to other parts of the body through them and cause cancer in those areas of the body too. Once the cancer has spread throughout the body it leads to death within a few years as the cancer takes over the healthy cells. Mutations in proto-oncogenes and tumor suppressor genes can cause liver cancer, which can be slowed down with treatments

Gene mutations are permanent alterations in the DNA sequence that make up the gene. They can affect a single base pair or part of a chromosome depending on the size of the mutation. Mutations occur for several reasons: DNA does not copy correctly, external influences, gene flow, etc. Mutations can be helpful as it causes a high diversity of genes in the world that makes evolution and natural selection possible; but they mostly cause disorders. A mutation that can have no effect is a base substitution as sometimes, even if you change a letter it still codes into the same thing. However, the worst type of mutation is a base insertion and deletion as it could change the order of the sequence. In the diagram above, we are not able to establish what kind of mutation occurred, however we can see that there was an error in translation and Tyr mutated into IIe.

Moreover, it’s important to understand that gene mutation occurs in our cell all the time. Accordingly, the prevention of cancer is profoundly dependent on the p53 tumour suppressor protein, which is the process to eliminate excess, damaged or infected cells by apoptosis (Haupt 2003). But if the cell doesn’t die in the process of apoptosis, it may lead a person to developing a cancer. Oncogene are a sequence of deoxyribonucleic acid (DNA) that has been altered or mutated from its original form and induces cancer (Encyclopaedia Britannica 2017). Some people have high risk of developing cancer because they inherited mutations in certain genes (Cancer research UK 2014). Mutation are classified into two, inherited and acquired types of mutation, widely discussed below (ASCO 2017)

The beginning of cancer begins with defects in the cells DNA. When cancer starts, the cell goes through the p53 gene, a gene

Cancer is caused by a malignant growth or tumour as a direct result on the uncontrolled division of abnormal cells in any part of the body. There are more than 100 different types of cancer, which each type of cancer being named after the organ of its origin. Normal cells divide uncontrollably into hyperplasia, then again into dysplasia before finally turning into cancer, although at the hyperplasia and dysplasia stage,

Over the years, evidence has proven that any mutations on chromosomes whether they are broken, missing or repositioned is not just a side effect of cancer, but can be an increasing factor for

Among the many types of DNA damage, one of the most severe is DNA double strand breaks (DSB). DNA DSBs occur when two complementary strands break simultaneously generating two strands which are not being held together by base-pairing and chromatin structure. Few known causes for DSB are ionizing radiation, chemical mutagens, reactive oxygen species and drugs which are used for chemotherapy (Goodsell, 2005). This breakage can cause chromosomal rearrangement such as translocation and inversion, consequentially resulting in detrimental phenotypic affects.

When mutations in the genes accumulate over time in multiple genes that are in control of cell proliferation the cells become cancerous ("Cell Division and Cancer"). After this occurs the cells begin to grow and divide rapidly causing lumps called tumors to form ("How cancer starts"). The gene mutations that can cause breast cancer are many. Some common causes include mutations in proto-oncogenes which are genes that assist the cell in growing normally. When they mutate or are too abundant they can activate randomly causing cells to grow and multiply out of control. Another cause is inherited gene changes. These inherited DNA mutations cause increased risk for developing certain types of cancer such as breast cancer. For example those

In human cells, a combination of normal metabolic activities, errors in DNA replication, and external mutagens like radiation can lead to 1 million individual molecular lesions per cell per day. Therefore, DNA repair mechanisms are constantly active to help ensure that these molecular lesions do not lead to various diseases.

Effects of Mutations on the Human Body If the mutation affects the control processes of a cell, then it can lead to a cell dividing

These tumours are a result of mutation that occurs in the DNA of normal cells. Because of these mutations, the cells grow and divide at an increased rate. Gradually the healthy cells die while the abnormal cells continue to grow, thrive and gradually form a tumour.

Modification of damaged DNA seems to be an understudied subject, there is much to understand on the restoration of DNA damage, repair and DNA methylation. Genomic DNA can be modified by methylation but much of it is affected on a gene when silenced. When epigenetic modification has been implicated with cancer and aging it causes DNA methylation to also have an impact on the double strand of DNA analysis. Modification as such provoke deteriorating changes like aging found in multicellular organisms and DNA damage may magnify biochemical pathways that regulate a cells growth or control DNA replication with DNA repair. In the article “DNA Damage, Homology-Directed Repair, and DNA Methylation” written by Concetta Cuozzo, Antonio Porcellini, Tiziana Angrisano, et al. they hypothesize how DNA damage and gene silencing may induce a DNA double-strand break within a genome as well as when DNA methylation is induced by homologous recombination that it may somewhat mark its reparation through a DNA segment and protect its cells against any unregulated gene expression that may be followed by DNA damage. The experiments used to demonstration how gene conversion can modify methylation pattern of repaired DNA and when that occurs methylation is able to silence the recombined gene. When exploring the molecular mechanisms that link DNA damage and the silencing gene then there is an induced double strand break that can be found at a specific location or DNA sequence in where the

Nucleotide Excision Repair: This mechanism can repair the large change caused by the damage in the double helix of the DNA. The damage in the DNA is screened by the multienzyme complex, these set of enzymes scrutinizes for any kind of lesions that may appear on the double helix. These changes on the double helix are listed as; 1) Covalent Interaction of large hydrocarbons with DNA bases (such as carcinogenic molecules found in the toxic substances like smoke, tar etc.), 2) Dimers caused by the UV light from sun which causes pairing of pyrimidine bases, such as, T-T, T-C, and C-C.