Chromosome and Chromatid Damage, Repair, and MeasurementEhsan H. Balagamwala, C. Marc Leyrer, Jeffrey A. Kittel, and Alex Almasan

DNA, CHROMOSOME AND CHROMATID DAMAGE, REPAIR, AND MEASUREMENT

EHSAN H. BALAGAMWALA, C. MARC LEYRER, JEFFREY A. KITTEL, AND ALEX ALMASAN

Question 1

What are the phases of mitosis?

Question 2

What are the important events during each phase of mitosis?

Question 1 What are the phases of mitosis?

Answer 1

The distinct phases of mitosis are prophase, metaphase, anaphase, and telophase (Figure 3.1).

Figure 3.1 Representation of the phases of the cell cycle.

Hall EJ, Giaccia AJ. Molecular mechanisms of DNA and chromosome damage and repair (chap 2). In: Hall EJ, Giaccia AJ, eds. Radiobiology for the Radiologist. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012:135–153.

Question 2 What are the important events during each phase of mitosis?

Answer 2

Prophase: The chromatin undergoes thickening and chromosomes condense into light coils. By the end of prophase, the chromosome is in its most condensed form.

Metaphase: Two events occur simultaneously during the metaphases—chromosomes move to the center of the cell and the spindle forms. Once the chromosomes are stabilized at the equator of the cell, their centromeres divide and metaphase is complete.

Anaphase: The chromosomes move on spindles to the poles of the cell.

Telophase: Chromosomes congregate at the poles and begin to uncoil. The nuclear membrane reappears (disappeared initially during the prophase) and the chromosomes continue to uncoil until the nucleus regains its characteristic interphase appearance.

Hall EJ, Giaccia AJ. Molecular mechanisms of DNA and chromosome damage and repair. In: Hall EJ, Giaccia AJ, eds. Radiobiology for the Radiologist. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012:135–153.

Question 3

What is the importance of telomeres?

Question 4

What enzyme can regenerate telomeres? What is its importance in cancer biology?

Question 5

What types of DNA damage are induced by radiation?

Question 6

What is the most lethal form of DNA damage and why?

Question 3 What is the importance of telomeres?

Answer 3

Telomeres cap and protect the ends of chromosomes. Telomeres are repetitive DNA sequences comprised of the TTAGGG (in humans) DNA sequence that vary in total length from 1.5 to 150 kb. With each replication cycle, telomeric DNA is lost. Once all telomeric DNA has been lost, vital DNA sequences are at risk for being lost; therefore, the cell undergoes senescence. It is estimated that a cell can divide between 40 and 60 times before undergoing senescence (called the Hayflick phenomenon).

Question 4 What enzyme can regenerate telomeres? What is its importance in cancer biology?

Answer 4

Telomerase is a reverse transcriptase that contains an RNA component for the complementary sequence to the TTAGGG sequence repeats that it uses as a template to continually extend telomeres at the end of chromosomes. Telomerase is expressed in stem cells as well as cancer cells; however, it is not expressed at detectable levels in other normal human somatic tissues. Therefore, it is thought that immortalization and carcinogenesis are associated with telomerase expression. Approximately 90% of human cancer biopsies show expression of telomerase.

Question 5 What types of DNA damage are induced by radiation?

Answer 5

Radiation therapy (RT) induces several types of DNA damage: base damage, single-strand breaks, and double-strand breaks (most common to least common). The majority of RT-induced DNA damage is repaired effectively; if the damage is not repaired correctly, the cells can undergo apoptosis or acquire mutation(s) that can lead to carcinogenesis.

Question 6 What is the most lethal form of DNA damage and why?

Answer 6

The most lethal form of DNA damage is a double-stranded break (DSB). Single-strand breaks are of little biological consequence because the DNA repair mechanism utilizes the opposite strand to effectively and accurately repair the DNA damage. However, when a DSB occurs, DNA repair is more difficult. Unrepaired DSBs can lead to nonlethal DNA lesions such as deletions or translocations as well as the formation of lethal DNA lesions, including dicentrics, rings, and anaphase bridges.

Question 7

Which phase of the cell cycle is the most radiosensitive?

Question 8

What are the basic repair mechanisms for single-strand breaks?

Question 9

In what phase of the cell cycles does homologous recombination repair (HRR) and nonhomologous end-joining (NHEJ) occur?

Question 10

What are the essential steps in nonhomologous end joining (NHEJ)?

Question 7 Which phase of the cell cycle is the most radiosensitive?

Answer 7

G2 and M phases of the cell cycle are the most sensitive phases of the cell cycle. This is because during these phases of the cell cycle, chromosomes are actively dividing and the DNA is more “exposed.” In addition, cells may have already passed through the last cell cycle checkpoint so proceeding through replication results in “mitotic catastrophe.”

Plesca D, Crosby ME, Gupta D, Almasan A. E2F4 function in G2: maintaining G2-arrest to prevent mitotic entry with damaged DNA. Cell Cycle. 2007;6:1147–1152.

Vakifahmetoglu H, Olsson M, Zhivotovsky B. Death through a tragedy: mitotic catastrophe. Cell Death Differ. 2008;15:1153–1162.

Question 8 What are the basic repair mechanisms for single-strand breaks?

Answer 8

Base excision repair (BER) and nucleotide excision repair (NER) are important single-strand break repair mechanisms. In BER, a nucleotide base is removed and it is synthesized using the opposite strand as a template. NER removes bulky adducts created most frequently by UV damage. NER occurs via global genome repair and transcription-coupled repair. Mutations in BER and NER genes do not lead to ionizing radiation sensitivity.

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