genetics chp. 12

NHEJ

- Error prone system! quick and dirty!

mutation frequences :

- are low in all genomes - differ considerably amoung organisms - vary amoung genes of a single species

second-site reversion

- occurs by mutation in a different gene and together the two mutations restore the organism to wild-type

3 types of regulatory mutations are recognized:

- promoter - splicing - cryptic splice sites

how do dominant lethal alleles like Huntington stay in the gene pool?

- symptoms do not show until later in life after given a chance to reproduce.

what causes trinucelotide repeat disorders?

- wild-type alleles of the genes in question have a characteristic number of DNA trinucelotide repeats. - increases in the number of repeats beyond a certain threshold causes the disorders

x-rays and radio active materials have ___ energy than UV light.

- x-rays and radioactive materials have higher energy than UV light.

topisomerase II

-Makes transient breaks (cut) in BOTH strands so both NEGATIVE and POSITIVE supercoil can be relieved

alkylating agents

-common characteristic of forming bonds or linkages with DNA a process called alkylation - add bulky side groups such as methyl (CH3) and ethyl (CH3-CH2) groups to bases

how does the body fix nucleotide base excision ?

1) DNA glucosylase removes the modified nucleotide, leaving an AP site. 2) AP endonuclease excises the AP deoxyribose 3) DNA polymerase synthesizes new dan from the 3' oh site using the lower strand as a template 4) dna ligase seals the single-stander gap and reforms an intact duplex with the original sequence.

whats special about 5-BrdU?

5-BrdU are base analogs that are chemical compounds with structures similar to a DNA nucleotide. - they can pair with normal nucleotides - DNA polymerase cannon distinguish the analogs from normal nucleotides

splicing mutation

A mutation altering the normal splicing pattern of a pre-mRNA.

silent mutation

A mutation that changes a single nucleotide, but does not change the amino acid created. - a base-pair change that does not alter the resulting amino acid sequence due to the redundancy of the genetic code

nonsense mutation

A mutation that changes an amino acid codon to one of the three stop codons, resulting in a shorter and usually nonfunctional protein. - a base-pair change that creates a stop codon in place of a codon specifying an amino acid

Depurination

A mutation that occurs when a purine base (A or G) is removed from the sugar-phosphate back bone; effectively stops replication. - the loss of a purine from a nucleotide by breaking the covalent bond linking the nucleotide base to the sugar

missense mutation

A point mutation in which a codon that specifies an amino acid is mutated into a codon that specifies a different amino acid. - a base-pair change that results in an amino acid change in the protein

true reversion

A type of reversion that exactly reverses the original mutation. - wild-type DNA sequence is resorted by a second mutation within the same codon

___ plays a pivotal role in communicating DNA damage through signal transduction, to activate transcription of the ___ gene

ATM plays a pivotal role in communicating DNA damage through signal transduction, to activate transcription of the p53 gene

agents that cause DNA damage leading to mutations are called _______.

Agents that cause DNA damage leading to mutations are called mutagens

huntington disease

An autosomal dominant disease that is a progressive, neuro-degenerative disease causing uncontrolled physical movements, and mental deterioration. Chorea includes irregular, rapid, uncontrolled, involuntary, excessive movement that moves from one side of the body to the other - is caused due to trinucelotide repeats disorders which is caused by slippage during replication

DNA nucelotide bases can occasionally convert to alternative structures called _______, with slight differences in bonding and placement of hydrogens.

DNA nueclotide bases can occasionally convert to alternative structures called tautomers, with slight differences in bonding and placement of hydrogens.

What will DNA polymerase do after deprivation?

DNA polymerase will usually compensate by putting an adenine into the site during replication.

DNA replication has very high fidelity due to :

DNA replication has very high fidelity due to proofreading ability of DNA polymerase

photolyase is encoded by _______ (photo reactive repair) gene.

E.coli phr

Synthesis-Dependent Strand Annealing

Error-free repair of double-stranded breaks

__________ __________ (EMS) is a powerful alkylating agent

Ethyl methanesulfonate (EMS) is a powerful alkylating agent

how does double stranded break repair work?

Nonhomologous end joining (NHEJ) inevitably leads to mutation Sythesis-dependant strand annealing Similar to homolgous recombination

how does DNA Recombination repair work?

Recombination repair directs recombination of the incomplete segment with the complementary strand, using the sister chromatid as the repair template

induced mutations

Result from exposure to known mutagens, physical (primarily radiation) or chemical agents that interact with DNA in a disruptive manner. - a produced by interactions between DNA and physical, chemical, or biological agents that generate mutations.

______ _______ leads to re-replication of some of the repeats and an overall increase in the number of repeats on the daughter strand.

Resumption of replication leads to re-replication of some of the repeats and an overall increase in the number of repeats on the daughter strand.

p53 pathway

Slows the G1 to S cell cycle transition in the event of DNA damage

_____ ______ in regions of repeating DNA sequences leads to an altered number of repeat elements.

Strand slippage of repeating DNA sequences leads to an altered number of repeat elements.

deamination

THE REMOVAL OF AN AMINO GROUP

_______ _____ is the most common form of replication error.

Tautomeric shifts is the most common form of replication error.

strand slippage

______ occurs when one nucleotide strand forms a small loop that bunches up

tautomers

a class of isomers of the nucleotide bases that cause the change of location of 1 single hydrogen

transversion mutations

a pyrimidine is replaced by a purine or vice versa

How does the body fix UV repair?

a short segment of DNA surrounding the photoproduct is excised then new DNA is synthesized to replace the removed nucleotides.

hydroxylating agents

add hydroxyl groups to bases of nucleotides (type of chemical mutagen)

proflavin

an intercolating agent that blocks DNA polymerase

an unrepaired lesion of deprurination is called an _______ ________.

an unrepaired lesion of deprivation is called apurinic site

what is the result of these bulky adducts given from alkylaitng agents?

bulky adducts interfere with DNA base pairing and distort the DNA double helix

trinucleotide repeat disorders

caused by slippage during replication. Leads to Huntington's disease and fragile X syndrome - a special class of mutations causing some hereditary diseases in humans and other organisms

reverse mutations

change from mutant to wild type - convert mutant alleles to wild-type or near wild-type

how is damage by alkylating agents repaired?

damage by alkylating agents are repaired by enzymes that remove the added chemical groups, resorting the nucleotide to its normal form.

Pyrimidine dimers

damage caused to DNA by UV rays

regulatory mutations

disrupt normal regulatory processes and inappropriately activate or inactivate expression or a gene

intercalating agents

distort DNA to induce single nucleotide pair insertions and deletions

during DNA replication erros the DNA polyerase of the replisome ________ dissociates from the template and a portion of the newly replicated DNA forms a _________ _______.

during DNA replication errors the DNA polymerase of the replisome temporarily dissociates from the template and a portion of the newly replicated DNA forms a temporary hairpin

gene mutations may arise from _______ _______.

gene mutations may arise from spontaneous events

gene mutations ______, ______, or _______ one or more DNA base pairs.

gene mutations substitue, add, or delete one or more DNA base pairs

genomic regions containing repeat sequences experience higher degrees of errors during replication (hotspots of mutation) due to _____ ________.

genomic regions containing repeat sequences experience higher degrees of errors during replication (hotspots of mutation) due to strand slippage

whats one reason for mutational hotspots?

large gene size

localized mutations or, _______ ________, occur at a specific, identifiable position in a gene.

localized mutations, or point mutaions, occur at a speciec, identifiable position in a gene.

what happens when mutagens interact with DNA?

mutagens intreat with DNA in specific ways to cause particular types of sequence changes.

transition mutaions

one purine replaces another, or one pyrimidine replaces another

PRoflavin and Benzo(A)pyrene are ______ ______.

proflavin and benzo(A) pyrene are intercalating agents

__________ _________ interfere with efficient transcription initiation.

promoter mutations interfere with efficient transcription initiation.

some _______ ________ cause mild to moderate reductions in transcription levels, whereas others may abolish transcription

some promoter mutaions cause mild to moderate reductions in transcriptions levels, whereas others may abolish transcription

cryptic splice sites

splice sites who DNA's sequence differ slightly from normals splice sites, are usually unused and hidden within the eons - base-pair substitiuion mutations that produce new splice sites that replace or compete with authentic splice sites during mRNA processing.

tautomeric shifts

spontaneous changes in nucleotide base structure that interconvert amino/imino groups and keto/enol groups - tautomeric shifts can lead to base-pair mismatches and incorporation of incorrect bases during replication

spontaneous mutations arise primarily through...

spontaneous mutations arise primarily through errors in DNA replication or spontaneous changes in the chemical structure of a nucleotide base.

the enzyme _______ uses energy from visible light to break the bonds between pyridine dimers.regarding repair of UV-induced photoproducts.

the enzyme photlayse uses energy from visible light to break the bonds between pyrimidine dimers

how does x-rays and radioactive materials cause damage?

the most serious damage are single-stranded or double -stranded breaks in DNA

how is mutation frequency quantified in sexually reproducing diploids?

the number of mutation events in a given gene over a defined period of time (most often per DNA replication cycle or per cell generation)

how is mutation frequency quantified in bacteria and other haploid organisms?

the number of times mutation alters a particular gene

base-pair substitution mutation

the replacement of one nucleotide base pair by another

Double stranded breaks in DNA can block _____ _________ and are dealt with by specialized repair systems.

these breaks can block DNA replication and are dealt with by specialized repair systems.

what happens when cytosine is deaminated?

when cytosine is deaminated an oxygen atom usually takes its place, converting the cytosine into uracil.

what happens when methylated cytosine is deaminated?

when methylated cytosine is deaminated a thymine base is produced.

promoter mutation

commonly results in dramatic decrease in amount of gene transcribed - mutations that alter consensus sequence nucleotides of promoters.

deaminating agents remove ____ _______ from _________ _________

Deaminating agents remove amino groups from nucleotide bases

Deamination of 5-methylcytosine leads to a __________ to ______ substituion

Deamination of 5-methylcytosine leads to a G-C to A-T substation

Deamination of Adenine produces ______, which can mispair and lead to A-T to G-C base-pair substations

Deamination of adenine produces hypoxanthine, which can mispair and lead to A-T to G-C base-pair substituions

apurinic site

during depurination: the site at which the covalent bond b/t the sugar and a purine is broken, and it usually occurs if water is present,

what are the steps to the repair of UV:induced photoproducts?

1) thymine dimer forms 2) photolyase binds the thymine dimer. 3) visible light energize photlyase 4) photolayse is released leaving repair DNA.

each species has an average mutation frequency; those with ________ genomes have, on average, _________ mutation frequencies

each species has an average mutation frequency; those with large genomes have, on average, higher mutation frequencies

intercalating agents fit between where and what are the consequences?

intercalating agents fit between DNA base pairs, distorting the DNA duplex; some can also form bulky adducts that contribute to DNA distortion - the distortion leads to DNA nicking that is not efficiently repaired, resulting in added or lost nucleotides

chemical mutagens can be classified by their modes of action on DNA. These are:

1) nucelotide base analogs 2) deaminating agents 3) alkylating agents 4) oxidizing agents 5) hydoxylating agents - intercalating agents

what are the 4 types of coding sequence mutations?

1) silent mutation 2) missense mutation 3) nonsense mutaion 4) frameshift mutation

hydroxylating agents such as _______ add _____ groups to bases

hydroxylating agents such as hydroxyl amine add hydroxyl groups to bases

intragenic reversion

occurs through mutation elsewhere in the same gene - additional mutation in a second location restores the reading frame

forward mutation

Changes the wild-type phenotype to a mutant phenotype - converts a wild-type allele to a mutant allele

pyrimidine dimers can be directly repaired by ________ _________, in bacteria, single-celled eukaryotes, plants and some animals (not humans)

pyrimidine dimers can be directly repaired by photo reactive repair, in bacteria, single-celled eukaryotes, plants and some animals (not humans)

_______ _______ affect regions such as promoters, introns, and the regions coding for 5'- UTR and 3'- UTR segments

regulatory mutations affect regions such as promoters, introns, and the regions coding for 5'-UTR and 3'-UTR segments

BRCA1

BRCA1 is the first gene implicated in inherited forms of breast and ovarian cancer susceptibility -generates DNA repair proteins

benzo(A)pyrene

Benzo(a)pyrene is bioactivated by CYP450 to an electrophile that binds to DNA. Leads to death, or somatic mutations (permanent, heritable changes)

nucleotide base analogs

Chemical compound with a similar structure to a DNA nucleotide that can pair with normal nucleotides, ex: 5-bromodeoxyuridine

chemical mutagens

Chemicals that cause genetic mutations

point mutations

changes in a DNA sequence caused by substitution of one nucleotide for another

in the creation of hydroxylaminocytosine misfiring with adenine can occur creating a _____ to ______ transition mutation.

in the creation of hydroxylaminocytosine misfiring with adenine can occur creating a C-G to T-A transition mutation

spontaneous mutations

-include base-pair substitutions, insertions, deletions, and longer mutations that occur during DNA replication, repair, or recombination - arise in cells without exposure to agents capable of inducing mutation

____________ mutations are easier to detect than ________ mutations and so are easier to study.

dominant mutations are easier to detect than recessive mutations and so are easier to study.

DNA nicking

effect of topoisomerase II inhibition

efficeint splicing of introns from mRNA requires:

efficeint splicing of introns from mRNA requires specific sequences at either end of the intron

mutation frequencies for some genes are considerably higher than others in a given genome; gens that have elevated mutation frequencies are called ________ ____________ _____.

mutation frequencies for some genes are considerably higher than others in a given genome; genes that have elevated mutation frequencies are called hotspots of mutation

frameshift mutations

mutation that shifts the "reading" frame of the genetic message by inserting or deleting a nucleotide - insertion or deletion of one or more base pairs leads to addition or deletion of mRNA nucleotides, altering the reading frame of the message - the wrong amino acid sequence and premature stop codons are produced downstream of the altered nucleotides

_________ __________ are produced by the formation of one or two additional covalent bonds between adjacent pyrimidine nucleotides

pyrimidine dimers are produced by the formation of one or two additional covalent bonds between adjacent pyrimidine nucleotides