Point mutations

Point mutations change

a single nucleotide

Point mutations cause changes, types of point mutations

in protein-coding sequences can lead to changes in the protein sequence

• “silent” mutations do not change the protein sequence (e.g. variation in the 3rd base of many codons)

• “missense” mutations change the amino acid sequence

• conservative mutations change to a similar amino acid

• “nonsense” mutations create a stop codon

Point mutations can be caused by

DNA polymerase errors

• Select the wrong nucleotide

• Failure to remove incorrect nucleoside during proofreading

Mismatches can be caused by

tautomers

regular vs tautomer form

1. Nucleotides have tautomer forms capable of favorable interactions in the active site of DNA Polymerases

2. The predominant form of A can incorrectly base-pair with C and can be rejected due to incorrect geometry of H-bonds in the polymerase or can be removed by proofreading The tautomer form of A can base-pair with C and is similar in geometry to a C-G, so is less likely to be rejected or removed by proofreading.

3. The tautomeric C can pair with A and also mimics a correct C-G base pair

regular vs tautomer form 1

Nucleotides have tautomer forms capable of favorable interactions in the active site of DNA Polymerases

regular vs tautomer form 2

The predominant form of A can incorrectly base-pair with C and can be rejected due to incorrect geometry of H-bonds in the polymerase or can be removed by proofreading

The tautomer form of A can base-pair with C and is similar in geometry to a C-G, so is less likely to be rejected or removed by proofreading.

tautomer C

The tautomeric C can pair with A and also mimics a correct C-G base pair

regular vs tautomer form picture

Mismatches can be caused by 2

tautomers

1. Nucleotide tautomers increase the likelihood of mutations during DNA replication

2. Nucleotide tautomers are capable of favorable interactions in the active site of DNA Polymerases

3. Tautomers are short-lived and can switch back to the dominant form before or after incorporation into the synthesized strand

4. If a tautomer is added to the nascent strand and the polymerase moves on, it will return to the dominant form. The mismatched base pair will cause an irregularity in the DNA double helix that cannot be fixed by DNA polymerase but can be detected by repair machinery.

tautomers increase likelihood of

Nucleotide tautomers increase the likelihood of mutations during DNA replication

nucleotide tautomers are capable of

Nucleotide tautomers are capable of favorable interactions in the active site of DNA Polymerases

tautomers lifespan

Tautomers are short-lived and can switch back to the dominant form before or after incorporation into the synthesized strand

what if tautomer is added

If a tautomer is added to the nascent strand and the polymerase moves on, it will return to the dominant form.

The mismatched base pair will cause an irregularity in the DNA double helix that cannot be fixed by DNA polymerase but can be detected by repair machinery.

Point mutations can arise due to

mutagens or spontaneous processes

• Cytosine is spontaneously deaminated to form uracil which will base-pair with A in transcription and replication

• Guanine is oxidized to 8-oxoguanine in the presence of reactive oxygen species (a normal byproduct of electron transport in metabolism). 8-oxoG can base-pair with C or A in transcription and replication

Point mutations can arise due to 1

mutagens or spontaneous processes

Point mutations can arise due to 2 cytosine

Cytosine is spontaneously deaminated to form uracil which will base-pair with A in transcription and replication

Point mutations can arise due to 3 Guanine

Guanine is oxidized to 8-oxoguanine in the presence of reactive oxygen species (a normal byproduct of electron transport in metabolism).

8-oxoG can base-pair with C or A in transcription and replication