YIJC [H2] CI2.8 Molecular Biology of Cancer

2024 JC1 BIOLOGY LECTURE NOTES CORE IDEA 2: GENETICS AND INHERITANCE TOPIC 2.8: Molecular Biology of Cancer Learning Outcomes: You should be able to: (o) (modified) explain the need to regulate the mitotic cell cycle tightly (knowledge that dysregulation of checkpoints of cell division can result in uncontrolled cell division and cancer is required, but details of the mechanism are not required) (p) identify the causative factors, including genetic, chemical carcinogens, ionising radiation and loss of immunity, which may increase the chances of cancerous growth (q) explain how the loss of function mutation of tumour suppressor genes, including p53, and gain in function mutation of proto-oncogenes, including ras, results in uncontrolled cell division (r) describe the development of cancer as a multi -step process that includes accumulation of mutations, angiogenesis and metastasis Use the knowledge gained in this section in new situations or to solve related problems. References: Campbell, N. A., Reece, J. B., et al. (2018). Biology A Global Approach (Eleventh Edition)  Chapter 12 Mitosis, p284 – 299  Chapter 13 Sexual Life Cycles and Meiosis, p304 - 317 Note: Some of these references (including previous editions) are available in our library. You may wish to borrow them or visit the links to supplement your reading when necessary. Lecture Outline 1 Introduction ................................ ................................ ................................ ............................ 2 2 Checkpoints In The Cell Cycle ................................ ................................ .............................. 4 3 Causative Factors Leading To Cancerous Growth ................................ .............................. 7 4 Important Genes Controlling The Regulation Of Cell Cycle ................................ ............... 8 4.1 Proto-Oncogenes................................ ................................ ................................ ............. 9 4.2 Tumour Suppressor Genes ................................ ................................ ........................... 12 5 Multistep Model Of Cancer Development ................................ ................................ ........... 14 H2

2 1 Introduction The cell cycle is the sequence of events that occurs throughout the life of a cell, from its formation as a new cell by division, to its own division into two daughter cells.  A cell cycle that involves mitosis will give rise to genetically identical cells and this is important for growth, repair and the asexual reproduction of organisms.  This cycle is coupled intricately with DNA replication , which occurs during the synthesis phase of interphase. The cell cycle compromises of two main stages 1. Interphase: Comprises of G1 phase, S phase and G2 phase 2. Mitotic phase (M phase): comprises mitosis (nuclear division) and cytokinesis (cytoplasmic division) [Covered in Topic 2.3: Cell Division] Fig. 1: The Mitotic Cell Cycle Interphase  The longest phase of the cell cycle and a period of intense metabolic activity, where synthesis and growth occurs in preparation for cell division  Interphase can be divided into three subphases: o G1 phase (“first gap”) o S phase (“synthesis”) o G2 phase (“second gap”)

3 Checkpoint 1: RECAP What occurs during the different stages of interphase? G1 phase S phase G2 phase Asides from allowing the cell to grow, what do you think is the significance of G1 and G2 phases?

4 2 Checkpoints In The Cell Cycle The mitotic cell cycle is tightly regulated at various checkpoints that control the rate of cell division; uncontrolled cell division can result in cancer. Fig. 2.1: Checkpoints in the Cell Cycle The cell cycle is controlled at various checkpoints. These checkpoints are regulated by proteins such as cyclin-dependent kinases and cyclins. Such regulation which will lead to the activation and inhibition of other proteins to regulate the progression of cell division. Learning Outcome 2(o) modified: Explain the need to regulate the mitotic cell cycle tightly (knowledge that dysregulation of checkpoints of cell division can result in uncontrolled cell division and cancer is required, but details of the mechanism are not required)

5 Fig. 2.2: Overview of cell cycle control by cyclin-CDK complexes (you do not need to know the exact mechanism of how these proteins work) 2.1. G1 checkpoint, also known as Restriction point  Checks for presence of growth factors, nutrients, cell size and DNA damage before allowing the cells to proceed to the next phase. 2.2. G2 checkpoint also known as DNA replication checkpoint  Checks for DNA replication and DNA damage The G 2 checkpoint prevents cells from entering mitosis when DNA is not completely replicated or if DNA is damaged, providing an opportunity for repair and stopping the proliferation of damaged cells, hence the G2 checkpoint helps to maintain genomic stability. 2.3. Metaphase (M) checkpoint, also known as the spindle assembly checkpoint  Checks that chromosomes are all properly attached to the spindle fibres, to ensure that each daughter cell receives an equal set of chromosomes. Dysregulation of these cell cycle checkpoints can lead to uncontrolled cell division and proliferation (increase on cell numbers due to cell division), leading to cancer. S G2

6 Checkpoint 2: Significance of controlling the cell cycle via checkpoints Uncontrolled cell division and proliferation of cells often lead to the formation of tumours, hence leading to cancer. Using information from page 5, how does the dysregulation of each checkpoint possibly lead to cancer? [Hint, what is the function of each checkpoint?] Checkpoint Regulated check-point Unregulated checkpoint G1 checkpoint: Restriction point G2 checkpoint: DNA replication checkpoint M (metaphase) checkpoint: Spindle assembly checkpoint If the control system detects unfavourable internal or external conditions , it blocks progression through each of these checkpoints. Such delays are crucial because - Provide time for errors or malfunctioning cellular machinery to be repaired - Prevent errors in cell division that may result if cell cycle progressed prematurely to the next stage when conditions are still unfavourable

7 3 Causative Factors Leading To Cancerous Growth Cancer is caused by changes in a cell's DNA, i.e. mutations. Factors that result in such mutations are called causative factors of cancer . Factors may be genetic (hereditary), inherited from our parents, while others may be due to environmental factors. Environmental factors include chemical carcinogens (substances that can lead to cancer) , ionising radiation, infectious agents leading to loss of immunity etc. 3.1. Genetics (Hereditary) Genetics is a causative factor of cancer when defective alleles of genes are inherited from parents, resulting in increased predispositions to cancer in the offspring. As the cancer is due to an inherited gene mutation, it is referred to as hereditary cancer  E.g. children who inherited mutated BRCA1/BRCA2 genes has a higher risk of breast and ovarian cancer. 3.2. Chemical Carcinogens Chemical carcinogen causes mutations in DNA by forming covalent bonds with DNA to form DNA- carcinogen complex. This distorts the DNA double helix hence causes replication errors. It may also result in the removal of DNA nucleotides or cause DNA strands to break.  E.g.: tar in cigarettes 3.3. Ionising Radiation Ionising radiation causes mutations in DNA via strand breakages in the DNA backbone or through formation of pyrimidine dimers that led t