Lecture 6: Nucleic Acids

Werner’s Syndrome

autosomal recessive disease (both parents need copy) that causes premature aging around early adolescence or young adulthood; rare

what is a progeria disease

early onset aging

how common is Werner’s syndrome

1/100,000; more common in Japan - ¾ of all patients

pathology of Werners can be pinpointed to what

disruption of a single gene: wrn

wrn gene

helps break down polynucleotides (exonuclease), help remodel and repair DNA (helicase) and aids in interaction of DNA and proteins (RQC and HRDC domains)

Werners syndrome preclincally

tend to have shortened stature as well as lack of growth spurt as adolescents

when and what are the hallmark signs of Werners syndrome?

in early 20s they begin to develop mild cognitive impairment, cataracts, early greying of hair, skin changes (scleroderma)

clinical signs of Werner’s

develops in childhood/early adolescence - average age of diagnosis is late teens to early 20s but could be later

progression of Werner’s

osteoporosis, brain atrophy and dementia, cancers/neoplasms (includes a 50-fold increase in melanoma development) and atherosclerosis

regular functioning of Werner gene

major function is DNA repair - without proper functioning, DNA repair does not get corrected, leading to instability of the genome, affecting proper expression of other proteins

treatment of Werner’s

no good treatments

primary structure of genetic inheritance

nucleic acids, specially DNA

molecule’s structure

has specific 3D shape in aqueous environment which is highly regular and symmetrical

what is DNA x ray crystallography

form a crystal of any substance, send a beam of x-rays (photons) at the crystal, the pattern of diffraction (scattering) of rays give clues about structure

DNA-b structure

right-handed and clockwise direction

how does DNA transfer from parent to daughter cells?

DNA replication occurs during cell division, where the double helix unwinds and each strand serves as a template for the formation of a new complementary strand, leading to two identical DNA molecules.

DNA replication

DNA hybridizes if newly replicated DNA is hybrid molecular species, consisting of one-half parental material and one-half new DNA

does DNA always hybridize?

No, DNA hybridization occurs under specific conditions, particularly when newly synthesized strands incorporate parental DNA.

what shape is DNA

mostly found in the B-form because it is more stable in water, forms a stable bond with h-bonding in the minor groove of the molecule

what other shapes can DNA be found in

DNA can also be found in A-form, similar to B but is more compact (base pairs closer together), slightly wider double helix and angle of base pairs is tilted compared to b-form

denaturation

is the process where the double-stranded DNA molecule unravels into single strands due to breaking of hydrogen bonds, often due to heat or chemical agents - referring to as melting but not true melting as it does not turn to liquid; molecule ‘melts’ along h-bonds

what happens with DNA is denatured

separate into single strands and each random-coil strand has a higher energy than double helix

tertiary structure

folding of DNA/RNA in on itself

where is tertiary structure found in DNA

mostly in bacteria because the DNA is mostly circular (no chromosome), also found in mitochondria; more important for eukaryotes and RNA rather than DNA

quaternary structure

combination of DNA with histone proteins - helps to form chromosomes and other tightly wound structures

what if the nucleic acid is single stranded, how does this behave?

typically this is RNA rather than DNA - ‘hairpin’ structures formed by self-complementary sequences; the chain folds back on itself to make a stem-loop structure

example of hairpin loop

tRNA - has an amino acid on acceptor stem

what does melting depend on

the composition of the material: more G-C bonding = higher melting point, more A-T bonding = lower melting point - also occurs at very small temperature

why do G-C bonding and A-T bonding have different melting points?

G-C pairs form three hydrogen bonds, while A-T pairs form only two, making G-C bonding stronger and leading to a higher melting point

RNA polymerase

melts DNA template to create transcription bubble - process allows the enzyme to create polynucleotide from ribonucleotides