User:ChrisDumigan/sandbox

Chris Dumigan, Jeffrey Palmer, and David Wright will be working together to write an article on "Mutator genes". This will be the main sandbox.

Mutator Gene
A mutator gene is a gene that increases the rate of spontaneous mutations of other genes in the cell. Mutator alleles often have a mutation in a gene that encodes for proofreading proteins or helicases. Proofreading proteins will correct both the spontaneous and exogenous errors that happen in DNA from random internal events, and mutagens from the environment. When these proteins can’t properly repair DNA, the mutation rate is increased because the damages to DNA are allowed to replicate and create mutations. Many of the early discovered mutator genes are actually transposable elements.

Mutator genes have been shown to give an evolutionary advantage in strains of bacteria that live in a competitive environment. When organisms are in a highly competitive or dynamic environment, there are limited resources and organisms that can gain an adaptive edge through mutations will be able to live and pass on their genetic information. Mutator phenotypes have an increased chance to have a new method of survival because they are more likely to have mutant genes that give an adaptive edge in their environment. Although most mutations to genes are harmful, occasionally they can be beneficial and aid in the cell's survival. It has been suggested that cancer cells have a mutator phenotype because the amount of genetic mutations present would not arise without mutator genes. According to this hypothesis, cancer cells have mutations in genes that regulate the stability of the cell's genome, increasing the mutation rate and giving a chance for increased fitness in their environment. (See "Mutator phenotypes/genes and cancer" below)

History
Milislav Demerec reported in Drosophila melamogaster certain strains would have unstable genes that increase the rate of mutation in 1937. These genes Demerec was looking at would have varying mutation rates between tissues and stages of the organism's life cycle. Evidence that mutations usually result from natural cellular processes began to collect after these unstable genes were discovered.

The SOS response and inducible mutator genes
SOS response is induced by exogeneous factors that damage DNA such as UV light, or by amino acid, nutrient, or carbon starvation . Error prone DNA polymerases are produced when the SOS response is activated, causing increased mutations. RecA activates these polymerases, while LexA suppresses them. Three types of DNA polymerases are produced: DNA polymerase II (polBeta), DNA polymerase IV (dinB), and DNA polymerase V (umuCD).

Polymerase II is the first DNA polymerase produced after induction of the SOS response, and is highly precise at replicating DNA. Polymerase II likely doesn’t play a large role in mutating the genome, and functions to replicate DNA past damaged areas of the DNA.

DNA polymerase V is an error prone DNA polymerase, and plays the leading role in SOS mutagenesis. It replicates past damaged DNA in the SOS response, and is induced by RecA in response to DNA damage. It has also been shown to be produced in response to starvation.

Polymerase IV, DinB, is an error prone DNA polymerase, that is induced in conditions other than exogeneous DNA Damage. DNA polymerase IV is involved in adaptive mutagenesis, causing mutations in bacteria in response to starvation.

Mutator phenotypes/genes and cancer
Mutator genes have also been shown to be involved in tumor progression in cancer. A mutator gene causes mutations throughout a population of cells. A small proportion of these mutations will help those cells divide quickly. The cells with these mutations will divide and outcompete the cells that can’t grow as fast, resulting in the clonal expansion the cells with the growth advantage. This repeats for the next generation of cells – more mutations are accumulated, some of which make the cells divide faster. These cells will then spread faster than other cells, resulting in cancerous tumors with uncontrolled division.

RAG proteins and antibody production
The variable regions of antibodies are generated by genetic rearrangements, where separate V, D, and J gene segments are recombined during B cell development.

Recombination Activating Genes (RAG) are mutator genes involved in these somatic rearrangements. RAG proteins recognize DNA sequences that flank the V, D, and J regions, and create double stranded breaks . The segments are rejoined together by the RAG proteins, and other proteins involved double stranded break repair, creating genetic rearrangments .  The Rag genes are only expressed in the lymphocytes, which consists of B and T cells, both of which are involved in the immune response.

MutD
The MutD gene is made from mutations to dnaQ or the epsilon subunit of DNA polymerase III in E. coli, it's role is to proofread 3'->5' and exonuclease. MutD's mutation rates can vary due to media conditions, like thymidine concentrations, from 10-100 fold increase from wild types. E.C. Cox found that mutD is can cause a variety of mutations while other mut genes are specific, such as mutA/M/Y/T can only cause certain transversions and frameshifts while mutD can allow all base substitution mutations to occur. Mut gene's frameshift mutation rate can be increased by 2-5 fold with other polymerizing proteins, such as polA1, which can't polymerize effectively.

APOBEC family
The APOBEC family has 4 members: AID, APOBEC1, APOBEC2 and APOBEC3A-3H. They are regulated to mutate only specific regions of the genome, mRNA, or viral cDNA as a innate defense mechanism. AID (activation-induced cytidine deaminase) removes the amine group off cytosines making uracils(C->U), this APOBEC is regulated in the Immunoglubin(Ig) region of DNA which activates somatic hypermutation(SHM) and immunoglobulin class switching recombination(CSR) to create Immunoglobin(Ig) novelty. APOBEC1 and APOBEC3G are slightly different because they act on mRNA instead of DNA. APOBEC1 is focused on apolipoprotein B and neurofibromatosis type 1 mRNAs. APOBEC3G is an antiviral protein causing C/G to T/A transitions on retroviral cDNA and incorrect transcription/translation of viral proteins. However viruses such as HIV-1 have created a ubiquitylation factor for APOBEC3G, Vif, protecting its viral cDNA from APOBEC3G. This is one advancement viruses have taken to by-pass our natural immune system and become infectious.