Progeria and Lamin Mutations

• Cell genetic material can be damaged and repaired

Progeria and Lamin Mutations

• Progeria is characterized by premature aging and abnormal nuclear shape in cells
• Nucleus deformity in progeria results from defects in the nuclear lamina, which is made of lamin proteins
• A mutation in a lamin-encoding gene is responsible for Progeria
• There are three genes encoding lamin proteins: LMNA, LMNB1, and LMNB2
• Mutation in LMNA gene is responsible for progeria
• This mutation leads to aberrant mRNA splicing and nucleotide deletion from the exon of Lamin A
• The resulting truncated form of Lamin A protein is called progerin
• There is a deletion of 50 amino acids near the C-terminus in progerin

Lamin A vs. Progerin Processing

• Maturation of lamin A protein involves farnesylation, C-terminal cleavage, carboxymethylation and upstream cleavage
• Farnesylated progerin do not undergo the second cleavage and remain farnesylated
• Farnesylated progerin attaches to the nuclear membrane, disrupting the structural integrity of the nuclear lamina.
• Nuclear lamina disruption impacts activities that lead to cell death, tissue damage, and premature aging

Point Mutations

• Mutations affecting a single or few DNA base pairs are called point mutations
• Point mutations include insertion, deletion, and substitution of one or more base pairs
• Point mutations in the coding region can be silent, missense, nonsense, loss-of-stop, or frameshift mutations

Mutations and Protein Activity

• Loss-of-function mutations are often recessive such that only one mutated allele has no phenotypic effect
• Gain-of-function mutations are often dominant, meaning only one mutated allele has a phenotypic effect

DNA Replication Mutations

• Mutations can occur when bases are mispaired during DNA replication
• DNA polymerase makes approximately 1 mistake per 100,000 nucleotides copied
• DNA polymerase possesses a proofreading activity that removes mispaired bases
• With proofreading activity, DNA polymerase makes about 1 mistake per 10,000,000 nucleotides copied

Mismatch Repair

• Uncorrected mismatches will lead to a permanent mutation in one of the two DNA molecules produced by the next round of DNA replication
• Errors made during DNA replication must be corrected to avoid mutations
• The mismatch repair mechanism restores the original sequence
• Mismatch repair decreases the error rate to 1 mistake per 1,000,000,000 nucleotides copied

Depurination and Deamination

• Depurination and deamination are the most frequent chemical reactions known to create serious DNA damage in cells.
• Chemical modifications of nucleotides, if left unrepaired, produce mutations
• Deamination of cytosine, if uncorrected, results in the substitution of one base for another during DNA replication
• Depurination, if uncorrected, can lead to the loss of a nucleotide pair

Base Excision Repair (BER)

• Modified bases are removed by the base excision repair (BER) mechanism
• Base excision repair involves
  • Recognition of the modified base
  • Excision of the modified base
  • Removal of the corresponding nucleotide
  • Incorporation of the missing nucleotide
  • Ligation of the two adjacent nucleotides

Radiation

• UV radiation induces thymine dimers
• X-rays and y-rays cause single and double stranded breaks in DNA

Nucleotide Excision Repair (NER)

• Thymine dimers are repaired by nucleotide excision repair (NER) mechanism
• Nucleotide excision repair involves
  • Recognition of the thymine dimer
  • Excision of the damaged strand
  • DNA Polymerasization
  • Ligation

Chromosomal Rearrangements

• Double strand breaks can lead to chromosomal arrangements
• There are four types of such chromosomal rearrangements including deletions, duplications, inversions, and translocations

Double-Strand DNA Break Repair

• Double-strand DNA breaks can be repaired by nonhomologous end joining or homologous recombination