Question

Can a base-pair substitution mutation in a proto-oncogene lead to the production of an oncogene if it is in the wobble position of a codon that codes for leucine? Explain why or why not.

Answer 1

Proto-oncogenes are those genes whose activaion (by mutation) can give the capability of malignancy to cells, which is the basis of oncogenesis. Mostly gain-of-function mutation the proto-oncogenes will negatively regulate the apoptosis and leads to uncontrolled cell growth and cell division.

During translation, the codon triplet present in mRNA is read in 5' -> 3' polarity, when the anti-codon of tRNA is base-paired with it. It is immutable quality of base pairing that a purine always base-pair with the complementary pyrimidine base, and vice-versa. But there is an exception to this case (wobble in nature), hence the name 'wobble hypothesis'. The hypothesis states that only first 2 codon bases in mRNA have precise pairing with anti-codon bases in tRNA, while the 3rd base of cocon and anti-codon may "wobble". This wobbling phenomon allows a single tRNA (anti-codon) to pair with more than one codon. Though there are 61 codons for amino acids, number of tRNA in translation is far less due to this wobbling. For example, "AGG" of anti-codon usually binds with complementary pair "UCC", which translates to tryptophan, but due to wobbling "AGG" can also pair with codon "UCU", which translates to cysteine.

Main wobble pair involving the core bases is G-U. Other wobble pairing involves non-traditional base, hypoxanthine (I): I-U, I-A, I-C.

Coming the second part of question, when the wobble position of codon for leucine is mutated (base-pair substituion):

Codons exhibits property of degeneracy - more than 1 codon codes for an amino acid. Hence the codons coding for leucine are:

UUA, UUG, CUU, CUC, CUA, CUG.

If we notice closely, the 2nd base for all the codons are same. So, its only the matter with 1st and 3rd bases. When the 1st base is C, all the 4 possible bases in 3rd position also gives Leucine, which makes it a same-sense mutation. Hence there is no gain-of-function for proto-oncogene, means no oncogene activation.

When the 1st base is U, there are 2 possible bases A and G (both are purines) at wobble position coding for leucine. The complementary pair of A (i.e. U) can pair with A as well as G (in wobble pair).

(UUA - AAU) and (UUG - AAC and AAU)

When wobble base is mutated to a pyrimidine: UUA -> UUU or UUC (that's the only case when the main wobble pairs are not present) codes for amino acid phenylalanine (degeneracy) .

Hence the base-pair substitution with a pyrimidine base at wobble position of codon for leucine alone will make the proto-oncogene mutated. If the leucine -> phenyl alanine is a gain-of-function, then this mutation will activate the proto-oncogene to oncogene leading to malignancy.