Lecture 3

Question 1

What are the steps of detecting and repairing mismatches in the DNA?

Answer 1

First detection id sone by MutSalpha or beta. Then a nick is formed, the nucleotide is removed and the gap is filled by polymerase, ligase puts everything together

Question 2

What is the difference in MSH between MutS alpha or beta?

Answer 2

MutS alpha: MSH 2 and 6
MutS beta: MSH 2 and 3

Question 3

What is the consequence of a mismatch mutation in MMR gene?

Answer 3

It causes Lynch syndrome, or hereditary non-polyposis colorectal cancer. MMR mutation is autosomal dominant

Question 4

What is the process of nucleotide excision repair?

Answer 4

The helix-distorting DNA lesion is removed (eg adducts). Which is either done via global genome or transcription coupled NER. The DNA is opened by helicases and endonucleases remove the desired part

Question 5

What does a mutation in the NER genes lead to?

Answer 5

It causes Xeroderma pigmentosum (XP)

Question 6

What is Xeroderma pigmentosum?

Answer 6

You are hypersensitive to sunlight and have a high risk of skin cancer

Question 7

When is base excision repair used?

Answer 7

When nucleotides are damaged due to intracellular processes eg 8-oxo-guanine. Or to repair ssDNA breaks

Question 8

What is the process of base excision repair (BER)?

Answer 8

DNA glycosylase detects the site (get abasic site when only the base is removed), endonuclease then cleaves the backbone and flap endonuclease removes the flap

Question 9

What is MUTYH?

Answer 9

It is a DNA glycosylase that repairs 8-oxo-guanine

Question 10

What is the consequence of a mutation in MUTYH?

Answer 10

You get MUTYH associated polyps or familial adenomatous polyposis type 2. Thus a higher risk of colorectal cancer

Question 11

Which 4 different ways are there to repair dsDNA breaks?

Answer 11

Non-homologous or alternative end-joining, also single-strand annealing and homologous recombination

Question 12

What does the single-strand annealing rely on?

Answer 12

It relies on homologous repeat consequences, it leads to deletion

Question 13

What is needed for homologous recombination?

Answer 13

Need a template from the sister chromatid

Question 14

What is the process of homologous recombination?

Answer 14

ATM senses a break, exonuclease of the MRN complex digests the damaged strands to expose the ss regions. RAD51 then searches for homology. Resolvase is also involved in restoring

Question 15

Which cancer predisposition syndromes are related to repairing dsDNA breaks?

Answer 15

Ataxia telangiectasia (leukemia and lymphoma), nijmegen breakage syndrome (lymphoma), bloom’s syndrome (all), BRCA1/2 (breast, ovary, pancreas)

Question 16

Why are BRCA1 carriers promising for therapy?

Answer 16

There is a defect in homologous recombination in the tumor, but not in the normal cell

Question 17

When is an intrastrand crosslink repair done?

Answer 17

Also called Fanconi Anemia , it’s a dsDNA break during cell division

Question 18

How do repair an intrastrand crosslink and what are the consequences/risks?

Answer 18

Repair is done via homologous recombination. Is a consequence of chemo and have a higher risk of leukemia, head/neck cancer

Question 19

How do you combat cancer?

Answer 19

By inducing DNA damage

Question 20

How many cancer patients usually get radiotherapy?

Answer 20

About 50 percent

Question 21

What are adverse events of radiotherapy?

Answer 21

Toxicity in normal cells, carcinogenic, therapy resistance

Question 22

What is the benefit of ionizing radiation?

Answer 22

It can be a cure and give diagnostic information

Question 23

What is the risk of ionizing radiation?

Answer 23

Tissue or organ injury, teratogenic, genetic and carcinogenic effects

Question 24

What does the chemotherapy platinum-based drug do?

Answer 24

It induces crosslinks (eg cisplatin and carboplatin)

Question 25

What does the chemotherapy alkylating agents do?

Answer 25

It adds DNA adducts via alkyl, requires metabolic activity (eg chlorambucil)

Question 26

What does the chemotherapy antimetabolites do?

Answer 26

They mimic endogenous substances, inhibit nucleic acid synthesis (eg methotrexate and 5FU)

Question 27

What does the chemotherapy topoisomere inhibitor do?

Answer 27

It increases the risk of DNA breaks (eg doxorubicin)

Question 28

What does the chemotherapy mitotic spindle poison do?

Answer 28

It prevents mitotic activity (eg vincristine)

Question 29

What is done with hormone therapy?

Answer 29

Cancers that need hormones for growth are targeted

Question 30

Which drug can interfere with hormone synthesis?

Answer 30

Aromatose inhibitor, which prevents adrogen to estrogen conversion

Question 31

Which drug can block the hormone receptor?

Answer 31

Tanoxifen to the ER to prevent estrogen binding

Question 32

How can intrinsic drug resistance occur?

Answer 32

The tumor cell is heterogenous (different sensitivity due to a mutation in the cancer stem cell). Or due to the distance from the blood vessel and the vascular density. Also hypoxic cells are radio-resistant and debolished drug

Question 33

How can acquired resistance occur?

Answer 33

Due to a higher drug efflux by the cancer cells or prevention of drug influx. Or amplifying of the target to outcompete the drug. Also modify the metabolism of the drug so it cannot become active. May enhance capacity to degrade the drug

Question 34

What is synthetic letahlity?

Answer 34

A mutation of 2 genes combined is lethal eg BRCA1 and PARP inhibitor (use it to kill the cancer cells)