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MUTATIONS AND DNA REPAIR MECHANISIMS

Types Of Mutations

• Spontaneous mutations: occur because of natural processes in cells, for example DNA replication errors.

• Induced mutations: occur because of interaction of DNA with an outside agent or mutagen that causes DNA damage.

  1. the importance of mutations 

  2. genetic variation 

  3. deleterious or advantageous 

  4. mutations in germ cells can lead to heritable genetic disorders.

  5. mutations in somatic cells may lead to acquired diseases such as cancer or neurodegenerative disorders. 

  6. tools for molecular biologists in characterizing the genes. 

• Mutations that alter a single nucleotide pair are called point mutations. 

Other Kinds of Mutations 

expansions of trinucleotide repeats, 

extensive insertions and deletions

major chromosomal rearrangements

metin, ekran görüntüsü, yazı tipi, sayı, numara içeren bir resim Açıklama otomatik olarak oluşturuldu

• Transition mutations replace one pyrimidine base with another, or one purine base with another. 

• Transversion mutations replace a pyrimidine with a purine or vice versa.

Sickle cell anemia mutation is an AT → TA transversion.


Expansion Of Trinucleotide Repeats Leads to Genetic Instability

•Dynamic expansion of trinucleotide repeats leads to certain genetic neurological disorders such as fragile X syndrome, Huntington’s disease, Kennedy’s disease, Friedreich’s ataxia, spinocerebellar ataxia type 1, and myotonic dystrophy.

General classes of DNA damage

  1. Single Base Changes

•Replacement of the amino group of cytosine with oxygen converts cytosine to uracil, a base that should only be present in an RNA chain. 

•This type of conversion process is called deamination. 

•Deamination is the most frequent and important kind of hydrolytic damage, and can occur spontaneously from the action of water, or be induced by a chemical mutagen. (Nitrous acid, sulfonates (alkylators), nitrosoguanidine) 

•Vertebrate DNA frequently contains 5- methyl cytosine in place of cytosine. 

•Methylated cytosines (alkylation) are hotspots for spontaneous mutations in vertebrate DNA because deamination of 5-methylcytosine generates thymine. 

•This results in the change of a GC base pair into an AT when damaged DNA is replicated.

  1. Structural Distortion

• The most frequent UV-induced lesions of DNA are the induction of PYRIMIDINE DIMERS between two neighboring thymine bases by UV irradiation.

May inhibit transcription and replication by blocking the movement of polymerases.

• UV irradiation can also induce DIMERS BETWEEN CYTOSINE AND THYMINE.

• Other bulky adducts (DNA-Structural distortion) can be induced by CHEMICAL MUTAGENESIS, e.g. by exposure to large polycyclic hydrocarbons or alkylating agents. • Diğer hacimli eklentiler (DNA-Yapısal bozulma) KİMYASAL MUTJENEZ tarafından tetiklenebilir; Örneğin. büyük polisiklik hidrokarbonlara veya alkilleyici maddelere maruz bırakılarak.

• DNA damage is also caused by INTERCALATING (inserting) AGENTS and BASE ANALOGS. • DNA hasarına aynı zamanda ARALIKLI (yerleşen) AJANLAR ve BAZ ANALOGLARI da neden olur.

• BASE ANALOGS are substitute (Exchange) for normal bases. • BAZ ANALOGLARI normal bazların yerine geçer (Değişim).

• Because of structural differences of BASE ANALOGS, inappropriate (wrong) base pairing is formed. • BAZ ANALOGLARIN yapısal farklılıklarından dolayı uygun olmayan (yanlış) baz eşleşmeleri oluşur.

  1. DNA Backbone Damage

• Backbone damage includes the formation of abasic sites (loss of the nitrogenous base from a nucleotide) and double-strand DNA breaks.

• Double-strand breaks can be induced by ionizing radiation (e.g. X-rays, radioactive materials) and a wide range of chemical compounds.

• Double-strand breaks are the most severe type of DNA damage since they disrupt both DNA strands.

DNA REPAIR SYSTEMS

metin, ekran görüntüsü, yazı tipi, sayı, numara içeren bir resim Açıklama otomatik olarak oluşturuldu

Lesion Bypass metin, ekran görüntüsü, yazı tipi, sayı, numara içeren bir resim Açıklama otomatik olarak oluşturuldu

•In the simplest of models, the replicative polymerase, being unable to bypass a lesion in the DNA either “falls off» the DNA or simply translocates (change the place) to downstream (clock wise) of the lesion to continue replication. 

• This allows for loading of another DNA polymerase capable of replicating the lesion.


metin, diyagram, ekran görüntüsü, çizgi içeren bir resim Açıklama otomatik olarak oluşturuldumetin, ekran görüntüsü, diyagram, yazı tipi içeren bir resim Açıklama otomatik olarak oluşturuldu

•A key feature of each of these pathways is that MULTIPLE DYNAMIC PROTEIN INTERACTIONS are involved in the repair process. 

•THE DNA REPAIR PROTEINS ARE MODULAR, COMPOSED OF MULTIPLE STRUCTURAL DOMAINS WITH DISTINCT BIOCHEMICAL FUNCTIONS. 

•There are two main pathways for repair of single base changes: 

  1. Base Excision Repair 



metin, ekran görüntüsü, tasarım içeren bir resim Açıklama otomatik olarak oluşturuldu


  1. Mismatch Repair metin, ekran görüntüsü, yazı tipi, diyagram içeren bir resim Açıklama otomatik olarak oluşturuldu

  1. recognition of the error. 

  2. A single strand break by the exonuclease EXO1

  3. removes the portion of the strand 

  4. replace by DNA polymerase δ 

  5. DNA ligase I seals 







  1. Nucleotide Excision Repair

metin, menü içeren bir resim Açıklama otomatik olarak oluşturuldu





  1. Double-Strand Break Repair

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