Mutagenesis is a technique used in molecular biology to create mutant genes, proteins, and organisms. Therefore, this can result in deletions and insertions. It brings two ends of DNA fragments together and doesn't require homologous sequences. Otherwise, NHEJ is a repair mechanism for double-stranded DNA breaks. However, it comes at the expense of lower replication fidelity and high error rates, resulting in a greater likelihood of base substitutions. TLS involves DNA polymerases with larger active sites that allow them to tolerate and bypass DNA lesions. One mechanism to accomplish this is the TLS system. Therefore, it is often beneficial to circumvent these replicative arrests to promote cell survival. Failure to restart replication can result in double-stranded breaks, chromosomal rearrangements, and cell death. During DNA replication, high-fidelity polymerases have difficulty passing damaged bases (e.g., pyrimidine dimers or crosslinked DNA), which will stall DNA replication. The TLS repair system and NHEJ are of interest to endogenous mutagenesis. For example, xeroderma pigmentosum (a rare autosomal recessive skin disorder that makes a person highly prone to developing skin cancer) is caused by a mutation in the NER pathway, resulting in a build-up of UV-associated damage. If any of these repair mechanisms go awry, a cell is predisposed to DNA damage. There are multiple DNA repair mechanisms, including MMR, base excision repair (BER), nucleotide excision repair (NER), translesion synthesis (TLS), homologous recombination (HR), and non-homologous end-joining (NHEJ) pathways. Errors in repair or mutations affecting the DDR network cause different cancers. Įrrors in DNA repair mechanisms: The DNA damage response (DDR) is a group of mechanisms that sense DNA damage and promote repair. These include splice site, promoter or enhancer sequence, and termination site mutations. For example, in some forms of B-thalassemia, a mutated splice site results in the use of cryptic splice locations, causing impaired B-globin synthesis. Other types of mutations exist outside of the coding sequence. These proteins may be shorter or longer, and protein function may be disrupted or altered (e.g., Duchenne muscular dystrophy). Ī frameshift mutation occurs through the addition or deletion of nucleotides not divisible by 3, resulting in the misreading of the downstream nucleotides. These protein products are truncated and frequently nonfunctional (e.g., cystic fibrosis). Ī nonsense mutation is when a nucleotide substitution results in a new stop codon, which includes UGA, UAA, and UAG (remember the mnemonic "U Go Away, U Are Away, and U Are Gone," respectively). Missense mutations have variable effects but can lead to a decreased or altered protein function (e.g., sickle cell disease). There are various types of mutations, such as silent, missense, nonsense, and frameshift mutations.Ī silent mutation is a nucleotide substitution that codes for the same amino acid therefore, there is no change in the amino acid sequence or protein function.Ī missense mutation is when a nucleotide substitution results in an amino acid change. It is noteworthy that not all DNA mutations will have an impact on protein synthesis or function. For example, a CGG repeat expansion in the FRM1 gene causes fragile X syndrome, while a fusion protein BCR-ABL results in chronic myeloid leukemia (CML). Otherwise, human disease is a result of a mixed assortment of insertions, deletions, duplications, inversions, expansions, fusions, and complex rearrangements. An example is sickle cell disease, where a single base-pair mutation results in glutamate to valine amino acid substitution. Single base-pair substitutions are the most common cause of human pathology. Mutagenesis is the driving force of evolution however, it can also lead to cancers and heritable diseases. Furthermore, molecular genetic techniques, such as polymerase chain reaction (PCR), have revolutionized how mutations are obtained and studied. DNA consists of nucleotides that contain a phosphate backbone, a deoxyribose sugar, and one of four nitrogen-containing bases (adenine, guanine, cytosine, and thymine ). DNA mutagenesis occurs spontaneously in nature or as a result of mutagens (agents with a predisposition to alter DNA). A mutation is a permanent and heritable change in genetic material, which can result in altered protein function and phenotypic changes. Mutagenesis is the process by which an organism's deoxyribonucleic acids (DNA) change, resulting in a gene mutation.
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