Lec 7. Diseases associated with defects in DNA replication,repair and recombination Flashcards
What is replication stress?
Defined as slowing or stalling in replication fork progression
Pertaining to replication stress from endogenous and exogenous sources, what happens?
Causes genomic instability.
What is a Hallmark of Cancer?
Abnormal DNA structures if not resolved can be transmitted to the next gen in the form of DNA lesion resulting in genome instability.
What do telomeres do?
Protect the end of chromosomes
What happens in short telomere syndromes (STS)?
Accelerated aging by inheritable gene mutations resulting in decreases telomere lengths.
What is usually affected with STS?
Organs with high cell turnover, Bone marrow, liver, lungs, and immune systems are commonly affected.
What is telomerase?
Enzyme complex (DNA pol) that makes new telomere sequences onto the ends of chromosomes
What is DKC (Dyskeratosis congenita)?
Congenital disorder with a highly variable phenotype. Characterized by short telomeres.
What are clinical manifestations of DKC?
Abnormal skin pigmentation, nail dystrophy
What is a major consequence to DKC?
progressive bone marrow failure.
Why is genetic variation critical for evolutionary change?
Adaptation to new environments.
What happens in stressful conditions, where adaption might be necessary to survive?
Induce increase mutation in bacteria
what are some phenotypes for XP (Xeroderma pigmentosum)?
Skin cancer, UV sensitivity and neuro abnormalities.
What enzyme/process is affected with XP?
NER (nucleotide excision repair)
What are some phenotypes for AT (Ataxia telangiectasia)?
Leukemia, lymphoma, gamma ray sensitivity, genome instability
What enzyme/process is affected with AT?
ATM protein (kinase activated by ds breaks)
What are some phenotypes for bloom syndrome?
Cancer, stunted growth and genome instability
What enzyme/process is affected with bloom syndrome?
DNA helicase needed for recombination
What are the two major DNA repair pathways?
BER and NER
What disease is associated with a dysfunctional NHEJ?
SCID
True or False? Radiation increases mutation rates in all organisms?
True
What does Ionizing radiation do?
Dislodges e- in tissue causes free radicals which damage DNA
What does UV light induce?
Formation of pyrimidine dimers. 2 Thymine bases covalently bonded that blocks replication
What is the SOS system in bacteria?
Allows bacteria cells to bypass the replication block with a mutation prone pathway.
What do oxidative free radicals do?
Convert Guanine into 8-oxy..etc which mispairs with Adenine
How does the body repair the formation of pyrimidine dimers (two Thymines)?
Thymine dimer repair (NER). Dimer is repaired by enzymes that cut out the surrounding nucleotides and fill the space back in.
What is a good example of mismatch repair defects?
Mutations in the mismatch repair genes (tumer supressor genes) MLH1 and MSH2.
What happens when there is a mutation on the MLH1 and MSH2?
These genes get epigenetically turned off and result in microsatellite instability and genomic instability, implicated in some cancers.
What is the MGMT gene?
Gene crucial for genome stability. Repairs and prevents mismatch errors during DNA replication and transcription.
What are some characteristics for XP?
Sensitive to sunlight, abornmal skin pigmentation.
Why is skin cancer likely in XP?
Sunlight exposure produces pyrimidine dimers in skin cell DNA which cant be repaired
What repair system tackles UV induced DNA lesions?
NER
What is the ATM protein?
a kinase that responds to DNA damage by Phosphorylating key substrates involved in DNA repair and or cell cycle control
True or False? ATM mutations carriers that dont have AT are more likely than people without an ATM mutation to develop cancer
True
What are diagnosable characteristics for AT?
slurred speech, impaired motor skills and cerebellar dysfunction.
What is the most documented function of ATM?
regulating cellular response to DNA ds breaks
What are the most common mutations in Bloom Syndrome (BS) pts?
Nonsense or frameshift mutations in the BLM gene that cause trunction of the BLM protein.
What are some characteristics of pts with BS?
Small head, redness of cheecks, DM
What are RecQ helicases?
They unwind DNA for preparation of replication
How are BLM and BRCA 1&2 related?
BML works in combination with BRCA 1&2, all involved in DNA repair and talk with each other
