Mutations and mutagens

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Presentation transcript:

Mutations and mutagens

Transitions and transversions

Causes of transitions Agent (mutagen, etc.) Example Result Nucleotide analogs BrdUTP transitions, e.g. AT to GC Oxidizing agents nitrous acid transitions, e.g. CG to TA Alkylating agents nitrosoguanidine transitions, e.g. GC to AT

Causes of transversions Agent Example Misincorporation: Altered DNA Pol III mutD=dnaQ; e subunit of DNA PolIII transitions, transversions and frameshifts in mutant strains Result

Errors in Replication Origin: Source: Incorporate the wrong base spontaneous (naturally occurring) or forced (mutagenesis) Source: Incorporate the wrong base base or nucleoside analogs chemical modification of nucleosides Slippage during replication frameshift mutagens such as EtBr Breaks in phosphodiester backbone ionizing radiation Blockage in replication pyrimidine dimers induced by UV irradiation

Keto and enol tautomers of bases Tautomers of thymine Tautomers of guanine Recall keto to enol shift discussed in Figure 1.4.1b, p. 56

Enol conformation : causes incorporation of the wrong base Nucleotides in enol tautomer can pair with the “wrong” base Recall keto to enol shift discussed in Figure 1.4.1b, p. 56

Nucleoside analogs alter base pairing BrdU : an analog of dT Shifts into enol form more readily than dT

Replication of a misincorporated nucleotide will leave a mutation Br Br enol 1 U U G A + 2 T A C G + Br keto U A

imino-dA paired with amino-dC G:C base pair A:T base pair

syn-, amino-dA paired with anti-, imino-dA

Chemical modifications Also alter base-pairing Oxidative deamination Nitrous acid (HNO2) causes oxidation of C to U C to U also occurs spontaneously: 1 in 1000 C’s would change to U during a human lifertime, if not repaired Alkylating agents transfer methyl group to guanine

Oxidation of dC to dU allows pairing with dA

Oxidation products of dA and dG Either can pair with dC.

5-methyl-C is deaminated to dU --> T CH 3 CH 3 C to T transitions at CpG are the most common mutations in humans.

Alkylating agents Nitrosoguanidine derivatives, e.g. MNNG Cause methylation of G at O6 position and A at N3 Addition of the bulky group distorts the helix and causes mispairing

6-O-methyl G pairs with T G:C base pair A:T base pair

Intercalating agents are planar aromatic rings

Slippage during replication Intercalating agents can stabilize a loopout. 5’ 5’ 3’ Deletion in the daughter strand.

Ionizing radiation causes single-strand breaks X-rays, g-rays, b particles (electrons) cause single-strand breaks directly break phosphodiester backbone break imidazole ring of purines subsequent removal by glycosylase generates an AP (apurinic or apyrimidinic) site

UV radiation generates pyrimidine dimers Ultraviolet radiation (260 nm) a) Causes pyrimidine dimers between adjacent pyrimidines. The dimers can be of two types : 1) The major product is a cytobutane- containing thymine dimer (between C5 and C6 of adjacent T's) 2) The "6-4" photoproduct is also formed, and this causes the major mutagenic effect b) The pyrimidine dimers cause a distortion in the DNA double helix c) The dimers block replication and transcription

Structure of pyrimidine dimers d-ribose 5 6 (lose double bond; add H to C6)

Another view of cyclobutane pyrimidine dimers in DNA

6-4 photoproducts of thymine dimers

Causes of strand breaks Agent Example Result