L22: The Cell Cycle and Disease

Question 1

From what age does aneuploidy risk increase greatly?

Answer 1

34 years onward, occuring in 55-80% of embryos and 1-20% live births

Question 2

What are the possible disease outcomes for trisomies that survive to full term?

Answer 2

• Down Syndrome
• Edward’s Syndrome
• Patau’s syndrome

Question 3

Outline Down Syndrome

Answer 3

• 1 in 700 births
• trisomy 21
• common problems include upper respiratory infections, cardic abnormalities, speech/language difficulty & GI/ feeding b, behaviour, vision/ hearing problems

Question 4

Outline Edward’s Syndrome

Answer 4

• 1 in 3000 births being x3 more common in girls than boys
• trisomy 17 with poor life expectancy
• common problems inc kidney malfunctions, structural heart defects, intestines protuding outside body, mental retardation

Question 5

Outline Patau’s Syndrome

Answer 5

• 1 in 7600 births
• trisomy 13 with poor life expectancy
• common problems inc micropthalamia, extra digits, hypotonia

Question 6

What can permit proliferation of cell errors instead of apoptosis to get rid of them?

Answer 6

Defects in late G1/S (the start checkpoint) in DDR

- cells with damaged DNA are found in nearly all cancers

Question 7

What is the role of antimitotic drugs in chemotherapy?

Answer 7

To cause mitotic arrest, which can lead to

• unequal division
• death in mitosis
• exit without division then either cell-cyle progession (slippage), interphase arrest or death in interphase

Question 8

Explain the progession of the use of antimitotic drugs

Answer 8

• started with use of microtubule modifiers/ posions, in thought treated cells staying in mitosis for prolonged periods would undergo death
• however, extended neuronal cells depend upon integrity of microtubule network and so were susceptible to drug thus causing neuropathy

Question 9

Name some drug targets

Answer 9

• CDK1, AURKA1 B, PLK1 (older)

- PLK4, NEKs, Hapsin, MPS1, BUB1, BUBR1 (newer)

Question 10

What can depletion of Haspin by RNAi cause?

Answer 10

Chromosome alignment defects and failure of mitosis

Question 11

What is oncogene addiction

Answer 11

Observation that tumour cell, despite plethora of genetic alterations, can exhibit dependence on a single oncogenic pathway or protein for irs sustained proliferation and/or survival

Question 12

What is an implication of oncogene addiction?

Answer 12

Switching off this pathway should have dvasting effects on cancer cell while sparing normal cells

Question 13

Name pitfalls of chemotherapy

Answer 13

• cytotoxicity
• drug resistance: intrinsic (heterogenous cell population within tumour) or acquired (becoming more prevalent with more effective treatments)

Question 14

Explain looking at DDR as alternative approach to chemotherapy?

Answer 14

• DNA can be damaged by chemo/radio potentiation. PARP used to promote DDR induced by IR, TMZ and topo1 poisons allowing cell to survive
• If PARP inhibited then repair is insufficient

Question 15

Explain synthetic lethality in HRR- defective cells as an alternative approach to chemotherapy

Answer 15

• Synthetic lethality in HRR-defective cells: BER (base excision repair) and HRR (homologous recombination repair) complement each other in repair of endogenous DNA damage. Loss of BRCA1/2 can lead to genomic instability & tumour development
• Such tumour cells become more reliant on PARP so when PARP is inhibited cell cannot repair DNA sufficiently and dies. Normal cells that retain HRR function will survive even tho PARP is inhibited

Question 16

Name other diseases caused by defects in the cell cycle

Answer 16

• sub chromosomal structure: from loops to TADs
• cohesinopathies: gene expression control
• CdLs: autosomal dominant neurodevelopmental disorder (1 in 10,000). Characterised by mental retardation, facial dysmorphism, upper limb abnormalities & growth delay
• Roberts syndrome: autosomal recessive related phenotypically to CdLs w affected patients having craniofacial abnormalities, limb reduction & growth retardation
• Alzeihemer’s: re-entering cell cycle which leads to apoptosis progressively