FOM 5.2.1 Flashcards
Who is the famous actress that used prophylactic surgery to reduce her risk of cancer upon finding out that she had a mutation in BRCA1 or BRCA2?
Angelina Jolie (Sean’s Queen)
As doctors, we are concerned with survival. This often means we promote genomic stability. What might this adversely affect?
Our evolution as a species
What is the difference b/t a somatic and germline mutation?
Somatic: only affects individual Germline: mutation in cells that produce gametes, offspring will have mutation
What are three overarching sources of DNA damage?
Physical, chemical, copying errors
A light-skinned woman of European descent (Miles’ mother) sits in direct sunlight for an hour, how many damaging events occurred in the DNA of a typical skin cell on her face?
4000 for normal humans (however, Miles’ mother is goddess and thus isn’t susceptible to mutations)
What are the two types of chemical mutagens?
DNA adducts, free radicals
What are two common results of DNA adducts?
altered base pairing and dsDNA breaks
Cisplatin, a DNA cross-linking drug, can cause what two types of cross-links?
Intrastrand, Interstrand
What makes UVB worse than UVA? What do both types of UV create?
UVB is in the range of maximum absorbance of DNA; both create ROS
What type of mutation is produced by UV light?
thymidine (which is pyrimidine nt) dimers
What type of mutations are caused by ionizing radiation?
ssDNA and dsDNA breaks
What are the three steps of proofreading (which helps to reduce mistakes during DNA replication)?
Stop, Backtrack w/ a 3’-5’ exonuclease, Continue on again
What are the 3 steps of DNA lesion repair?
1) Recognize lesion 2) Remove lesion 3) Fill in gap
What are the two types of small lesions? What are the repair mechanisms for each?
What are the three types of complex lesions? What are the repair mechanisms for each?
What are the two repair methods for dsDNA breaks? Which is preferred?
Homologous recombination repair (preferred), Non-homolgous end joining
What repair mechanism is disrupted in Lynch Syndrom (hereditary nonpolyposis colorectal cancer)?
mismatch repair, congenital absence of any one of the four proteins involved in repair
What dz’d state is associated with defect in nucleotide excision repair?
Xeroderma Pigmentosum (XP)
What dz’d state is associated with defect in ICL repair?
Fanconi’s anemia, a defect in one of the 13 proteins involved
What the two main clinical manifestations/challenges of Fanconi’s Anemia?
Bone marrow failure and various forms of leukemia
Homologous recombination is often referred to as what type of mechanism?
“Error-free”
What two restricting factors of homologous repair?
cell cycle phase (S and G2), presence of template strand
Along with having a defect in the ICL repair pathway, Fanconi’s anemia (FA) can have a defect in what type of repair?
Homologous recombination repair, which results in chromosome instability syndrome
What are the main steps of non-homologous end joining (NHEJ)?
Recognition, DNA end blunting, end joining synthesis (resulting translocations are noted in a number of leukemias)
If doctor’s tell both parents that a child shouldn’t be exposed to sunlight b/c it will increase severity, what type of mutation are they trying to prevent?
Pyrimidine dimers
Loss of Repair = _____
Many mutations (duh… have you even been paying attention)
What are two possible cellular results of chromosome instability syndromes?
cell death, neoplasia
To exploit a BRCA mutation, what would be a good protein to inhibit? Why?
Poly ADP-ribose polymerase 1 (PARP1). By inhibiting this, DNA lesions will not be marked for repair, which will lead to increased amount of dsDNA breaks. Since homologous repair is absent in BRCA mutation, non-homologous repair is employed. Excessive NHEJ can lead to fatal DNA damage.
