DNA Repair and How do Mutations Occur? Flashcards
1
Q
types of genetic diseases (4)
A
chromosome disorders
single gene disorders
multifactorial or complex
sex linked and mitochondrial
2
Q
Chromosome Disorders
4
A
Rearrangements/Translocations, Deletions, Insertions, Duplications
3
Q
Single Gene Disorders
3
A
Dominant, Recessive, Codominant
4
Q
Multifactorial or Complex
2
A
Multiple genes, gene-environment
5
Q
general categories of mutations (2)
A
somatic
germline
6
Q
Somatic mutation
A
non-inheritable
7
Q
somatic mutation example
A
cigarette smoking and lung cancer, p53 mutations
8
Q
germline mutation
A
inherited
9
Q
— entries in OMIM currently
A
12,000+
10
Q
causes of mutations (2)
A
spontaneous
induced
11
Q
Spontaneous Mutations
A
arise naturally during DNA replication (mitosis) or during meiosis
12
Q
Induced Mutations (2)
A
every day exposure
radiation
chemicals
13
Q
silent mutation
A
no change
14
Q
missense mutation
A
single amino acid change
15
Q
nonsense mutation
A
stop codon produced truncated protein
16
Q
transition
A
Pur/Pur or Pyr/Pyr
17
Q
transversion
A
Purine / Pyrimidine
18
Q
deletion or insertion
A
Extra or Missing amino acids
19
Q
frameshift mutation
A
Altered protein
20
Q
other types of mutations (4)
A
- Promoter/Enhancer - Nuclear Receptors
- Splice Site
- Expanded Repeat
- Transposons
21
Q
nomenclature of mutations
A
• Amino acid designations
• genomic (gDNA) vs. mRNA (cDNA) vs. protein
• coordinates
• substitution(s)
• example:
• A1215T alanine at postion 1215 in the protein is
changed to a threonine
22
Q
Alleles are
A
sequence variants of a gene
23
Q
You inherit one
allele of each autosomal gene from
A
your mother and one
from your father
24
Q
Single nucleotide polymorphisms (SNPs) are
A
single base
differences at a specific position in the genome
25
SNPs
| occurring within a gene (can) give rise to an
allele
26
There are
| --- of SNPs in the genome
hundreds of thousands (millions)
27
Maintaining the genetic stability that an organism needs for its survival requires (2)
an extremely accurate mechanism for replicating DNA
mechanisms for repairing the many accidental lesions that occur continually in DNA
28
Most such spontaneous changes in DNA are --- because they are immediately
corrected by a set of process that are collectively called --- ---
temporary
| DNA repair
29
Of the thousands of random changes created every day in the DNA of a human cell by
(4), only a few accumulate as mutations in the DNA sequence
heat, metabolic accidents, radiation of various sorts, and exposure to substances in the environment
30
For example, we now know that fewer than one in 1000 accidental base changes in DNA
results in a --- ---
permanent mutation
31
the rest are eliminated with remarkable efficiency by
DNA repair
32
The importance of DNA repair is evident from the large investment that cells make in
DNA enzymes
33
For example, analysis of the genomes of the bacteria and yeasts has
revealed that several percent of the coding capacity of these organisms is devoted solely
to
DNA repair functions
34
he importance of DNA repair is also demonstrated by the increased rate of mutation
that follows the
inactivation of a DNA repair gene
35
Many DNA repair
proteins and the genes that encode them
36
Many DNA repair proteins and the genes that encode them- which we now know operate
in a wide range of organisms, including humans- were originally identified in bacteria by
the isolation and characterization of mutants that displayed an increased mutation rate
or an increased sensitivity to
DNA-damage agents
37
DNA is a highly stable material (compared to RNA), but it is a complex organic molecule
that is susceptible to
spontaneous changes that would lead to mutations if left
| unrepaired even under normal cell conditions
38
DNA of each human cell loses about --- purine bases (adenine/guanine) everyday
due to their deoxyribose hydrolyzation of N-glycosyl linkages, a spontaneous reaction
called ---
5000
| depurination
39
A spontaneous deamination of cytosine to uracil in DNA occurs at a rate of about ---
bases per cell per day
100
40
DNA bases are also occasionally damaged by
| 3
• an encounter with reactive metabolites produced in the cell (including reactive forms of
oxygen, H2O2, -OH, and -O2)
• exposure to chemicals in the environment.
• ultraviolet radiation from sun can produce a covalent linkage between two adjacent
pyrimidine bases in DNA to form thymine dimers (presented later in this lecture)
41
Oxidative damage by
reactive oxygen species
42
Uncontrolled methylation (CH3-) by
the methyl group donor S-adenosyl-methionine
43
Hydrolytic attack
deamination and depurination
44
most frequent spontaneous chemical reactions
hydrolytic attack
45
Without DNA repair, spontaneous DNA damage would rapidly
| change
DNA sequences
46
About 3% of the C nucleotides in vertebrate DNAs
| are methylated to help in
controlling gene
| expression
47
When these 5-methyl C nucleotides are
accidentally deaminated, they form the natural
nucleotide
T
48
However, this T will be paired with G on the
| opposite strand, forming a
mismatched base pair
49
About one-third of inherited human disorders are
single base mutations
50
The spontaneous deamination products of A and G
are recognized as --- when they occur in DNA
and thus are readily (2)
unnatural
| recognized and repaired
51
base excision repair
unnatural bases are recognized and removed by a specific DNA glycosylase
52
(2) are the two most frequent
| spontaneous chemical reactions known to create serious DNA damage in cells
Deamination and depurination, hydrolytic reactions
53
Deamination
cytosine to uracil in DNA is estimated to occur at a rate of 100
bases per genome per day
54
Depurination
lose 5000 purine bases (A or G) per day in each cell due to thermal
disruption of their N-glycosyl linkages to deoxyribose
55
Pyrimidine (C or T) dimer formation
covalent linkage of two adjacent pyrimidines by UV light from the sun
56
These premutagenic lesions alter the structure
| of DNA and consequently (2)
inhibit polymerases
| and arrest replication
57
Dimers may be repaired by (2), but unrepaired
| dimers are mutagenic
photoreactivation
| or nucleotide excision repair
58
AP site (apurinic/apyrimidinic site)
a location in DNA that has neither a purine nor a pyrimidine base
59
what does a bread in DS DNA cause
```
delays
progression of
G1 to S phase
and from S to M
phase (through
G2) in the Cell
Cycle
```
60
little of the mammalian genome codes for
proteins (1.5% of exons) and has function (3.5% of highly
conserved sequences such as 5’ and 3’ UTR, functional RNAs and conserved protein binding site of the
DNA ) that this mechanism is apparently an acceptable solution to the problem of rejoining broken
chromosomes (deletion)
61
If each member of a chromosome pair carries the
same allele, then the individual is called
--- for that gene
homozygous
62
If each member of a chromosome pair carries a
different allele, then the individual is called
--- for that gene
heterozygous
63
The phenotype of a --- gene will be
| observed in the homozygous or heterozygous state
dominant
64
The phenotype of a --- gene will be observed
| only in the homozygous state
recessive
65
mendels laws (2)
principle of segregation
| principle of independent assortment
66
Principle of Segregation
Sexually reproducing organisms possess genes that
occur in pairs and that only one member of this pair is
transmitted to the offspring
67
Principle of Independent Assortment
Genes at differ loci are transmitted independently
68
homologous recombination
Genetic exchange between a pair of homologous
| DNA sequences
69
DNA breaks often occur from (2)
radiation damage or
| reactive chemicals
70
```
DNA breaks also arise from DNA replication forks
that become (2)
```
stalled or broken
71
Homologous recombination is a mechanism to (3)
* Accurately repair double strand DNA breaks
* Exchange bits of genetic information
* Assures accurate chromosome segregation during meiosis
72
Homologous recombination has common features in
| all
cells
73
what guides homologous recombination?
DNA base pairing
74
In the test tube base pairing of single stranded DNA
| drives
DNA renaturation or hybridization
75
DNA renaturation or hybridization is a
| (2) driven process
temperature and salt
76
High temperature
| drives
double stranded DNA into single stranded DNA
77
In cells that cannot survive at high temperatures, --- are used that bind tightly
to the DNA and hold it an open configuration to serve as a
template for DNA synthesis
single
| stranded DNA binding proteins
78
Double-strand DNA breaks can be repaired by (3)
• Non-homologous end joining without a template which
creates a mutation at the site where the DNA duplexes
are joined.
• Inadvertent joining of two segments from different
chromosomes that results in chromosomal
translocations, which often give rise to disease
• Homologous recombination repairs DNA double strand
breaks accurately without loss or alteration of the DNA
sequence
79
Cells carefully regulate the use of homologous
| recombination in
DNA repair
80
Repair involves a number of
proteins
81
The enzymes catalyzing repair are present at ---
| concentrations in the ---
high
| nucleus
82
A number of accessory proteins are involved in
control of repair
83
Loss of essential proteins needed for repair are generally
| --- events
lethal
84
Loss or alterations (mutations) of accessary proteins
| often leads to
cancer
85
steps of homologous recombination (2)
1) Repair double-stranded breaks accurately
| 2) Generate crossover in meiosis
86
--- --- are often formed during homologous recombination
Holliday junctions
87
Holliday junction
(cross-strand exchange)
two DNA strands switch partners between
two double helices
88
DNA is under constant pressure to
acquire changes in its
| DNA sequence
89
Most changes are repaired before they
| become a
stable part of the DNA that is subsequently
| passed on to daughter cells
90
Various types of mutations occur in DNA, some of which
| will give rise to
altered protein variants of any given
| gene
91
When mutations occur in somatic tissues, they cannot
| be ---, but can give rise to diseases such as ---
inherited
| cancer
92
When mutations arise in the DNA of the gametes, they
| will be
passed on to the offspring
