Lecture 8 - DNA replication, repair and disease

Question 1

What is the rate of nucleotide errors during replication that go unrepaired?

Answer 1

1 in 10^10

Question 2

What is the negative side effect of having so many different proteins involved in DNA replication and the regulation of DNA replication?

Answer 2

Every protein involved is a point where a mutation can occur and cause problem with DNA replication.

Question 3

What is telomerase?

Answer 3

Protein complex with RNA that produces repetitive telomere sequence at the ends of chromosomes.

Question 5

What are short telomere syndromes and what causes them?

Answer 5

Accelerated aging syndromes that are often caused by mutations that decrease telomere length.

Question 6

What what organs/tissues do short telomere syndromes most frequently affect?

Answer 6

Organs/tissues with high cell turnover rates such as bone marrow, liver, lungs, and the immune system.

Question 7

What are the most common clinical indicators of short telomere syndrome?

Answer 7

Premature graying of hair (under the age of 30)

Unexplained cytopenia

Idopathic pulmonary fibrosis

Cryptogenic cirrhosis

Question 8

What is the “hallmark of cancer”?

Answer 8

Genome instability caused by abnormal DNA structures that are not resolved properly and lead to DNA lesions in the next generation

Question 9

What are common causes of mutations?

Answer 9

Replication errors

Spontaneous chemical changes

Chemically induced

Radiation

Question 10

What complication is associated with the oxidation of guanine?

Answer 10

Forms 8-oxy-7,8-dihydrodeoxyguanine which can mispair with adenine.

Question 11

What complication occurs with ionizing radiation?

Answer 11

Production of free radicals which can damage DNA.

Question 12

What is Xeroderma pigmentosum?

Answer 12

Autosomal recessive disease which is typically caused by defective nucleotide-excision repair.

It results in acute sensitivity to light and increase risk of cancer 1000-2000x due to lack of ability to repair pyrimidine dimers.

Question 13

What are the clinical indicators of xeroderma pigmentosum?

Answer 13

Pigmentation (abnormal freckling)

Xeroderma (dry skin)

Skin cancer at a young age

Abnormal sensitivity to the sun

Question 14

What is ataxia-telangiectasia?

Answer 14

Autosomal recessive disease caused by mutation of the ATM gene which leads to an increased risk of cancer.

Question 15

What is the ATM protein?

Answer 15

A kinase that in response to DNA damage activates several proteins involved in DNA repair and cell cycle control.

Activated proteins include BRCA1 and BLM.

Question 16

What are the clinical indicators of ataxia-telangiectasia?

Answer 16

Cerebelar dysfunction manifesting between the ages of 1 and 4 as:

Gait and truncal ataxia

Head tilting
Slurred speech
Oculomotor apraxia and abnormal ocular saccades

Question 17

What is the p53 protein?

Answer 17

It is found to be mutated in over 50% of cancers.

It is affected by function of the ATM protein.

Question 18

Which complication is associated with UV light?

Answer 18

Pyrimidine dimer (thymine dimers) which block DNA replication.

Question 19

What is Bloom syndrome?

Answer 19

Autosomal recessive disorder caused by a mutation in the BLM gene causing truncation of the BLM protein.

Greatly increases risk of cancer; mean age of diagnosis is ~24 y/o

Average age of death before 30

Extremely rare; ~220 cases worldwide

Question 20

What are the clinical indicators of Bloom syndrome?

Answer 20

• disproportionally small head
• redness of the cheeks and nose
• paucity of subcutaneous fat
• chronic obstructive lung disease
• DM

Question 21

What is RecQ?

Answer 21

Helicase protein family that tumor suppressing functions. BLM is in this protein family.