Lecture Summaries | The DNA Damage Response as a Target for Anti-Cancer Therapy | Biology

The grading for this class will be based on participation during presentations and discussions, as well as on the following two assignments:

Mid-term Assignment

Due during Ses #10

This assignment will consist of writing an abstract for a research article. Students will be given a part of a research article (results, materials and methods and the figures). With these core parts of the research article, each student should write a comprehensive 250-word abstract that summarizes the results of the key experiments and the main conclusions. The abstract should aim to put the specific findings in a more general perspective, as well.

Final Assignment

Due during Ses #15

For the final presentations each student will be assigned a research article that describes the function of a critical checkpoint protein related to a human disease. Students will discuss the key figures and summarize the molecular functions of the protein described in the paper. Furthermore, the students will briefly discuss the function of this protein within the global DNA damage network that was discussed throughout the course. Lastly, the students will be asked to explain the clinical features of the related human disease (mentioned in the research article), based on the molecular details that were described in the paper. The presentations are scheduled for 15 minutes (10 minutes talk [7-8 PowerPoint slides], followed by a 5 minutes discussion). The presentation will be given to the entire group. Students will be encouraged to actively participate in the discussion following each presentation.

Lecture summaries.
SES #	TOPICS	LECTURE SUMMARIES
1	Introduction	At the first meeting, we will briefly outline the general requirements, the class schedule and administrative details. The instructor and students will introduce themselves. The instructor will then summarize basic aspects of cell cycle regulation and the DNA damage response network. We will introduce the different DNA damage checkpoints that evolved to protect cellular DNA from various sources of damaging agents with a special focus on differences between normal cells and cancer cells. Also, commonly used model systems and standard techniques will be introduced and discussed.
2	The cell cycle	We will discuss the basic cell cycle machinery, using two classic papers describing the principles of cellular proliferation. We will learn about the different stages of the cell cycle and understand their specific characteristics. During this session we will also discuss the molecular mechanisms that make cell cycle progression dependent on extracellular cues (such as growth factors). We will discuss mechanisms by which cancer cells can acquire the ability for autonomous growth.
3	Cell cycle control – the role of the tumor suppressor pRb in the G₁/S transition	It is essential that the different phases of the cell cycle are precisely coordinated and controlled so that one phase is completed before the next one can begin. Errors in coordination can lead to chromosomal aberrations—chromosomes or parts of chromosomes can be lost, rearranged, or distributed unequally between the daughter cells. This type of alteration is often seen in cancer cells. A profound understanding of (1) how cells determine when and how to multiply and of (2) how that process can go awry is fundamental for understanding the development of cancer. Furthermore, this knowledge is essential to enable scientists and clinicians to predict, prevent, or reverse a tumor's growth properties. This week we will discuss how cell cycle control genes were first identified using yeast as a model organism. We will also discuss the role of tumor suppressor genes in the control of cell cycle progression.
4	Cdk-regulation	We will discuss how the core cell cycle machinery is subject to regulation. Specifically, we will discuss the regulation of Cyclindependent kinases (the major driving forces of the cell cycle) by phosphorylation and dephosphorylation.
5	Checkpoint control of the cell cycle	We will discuss the multiple means by which the DNA damage-activated checkpoints regulate cell cycle progression in response to DNA damage. Both transcriptional and post-translational responses will be discussed using the assigned landmark papers.
6	p53 regulation	One of the most commonly mutated genes in human cancer is p53. We will discuss the important role of the prominent tumor suppressor gene p53 in the cellular responses to DNA damage. We will see that p53 has a dual role in the response to DNA damage. On one hand it can mediate cellular survival, by arresting the cell cycle and inducing the expression of genes involved in DNA repair. On the other hand p53 is a potent inducer of programmed cell death — apoptosis. We will discuss potential therapeutic strategies that build on the common loss of p53 in human malignancies.
7	The DNA damage checkpoint differs depending on cell cycle stage	We will dive deeper into the core mechanisms that control the cellular response to DNA damage. We will discuss different modes of regulation of the phosphatase Cdc25. Furthermore, we will analyze different types of repair strategies that are dependent on the cellular DNA content and thus on the cell cycle stage.
8	'To die or not to die' – the decision between repair and apoptosis	We will discuss two different possible outcomes after exposure to genotoxic agents, controlled by p53. We will use two papers to show that both repair of the damaged genome and activation of programmed cell death can be initiated by similar signaling pathways.
9	Structural insights into the DNA damage response	We will discuss structural insights concerning the molecular machinery that controls the DNA damage response. We will focus on Rad50, a member of the MRN complex, as well as MDC1 and its interaction partner H2AX. These proteins are involved in the very early stages of the DNA damage response and together form the structures that serve as an anchoring platform for downstream signaling molecules.
10	Field trip: visit to an MIT Biology Laboratory	Now that have gathered a solid background concerning checkpoint signaling, we will be introduced to the real methods. We will visit a molecular biology laboratory focused on studying DNA damage and the subsequent checkpoint response. Typical checkpoint assays will be demonstrated. We will examine different samples of untreated or damaged material that have been analyzed by FACS (Fluorescence Activated Cell Sorter) and by high-resolution fluorescence microscopy. We will analyze our data using the knowledge acquired in our prior sessions.
11	Defective DNA damage responses and cancer	We will learn about the importance of the DNA damage response by studying the impact of checkpoint failure due to mutations in critical checkpoint genes. We will discuss the consequences of loss of Chk1 and p53. Both papers use the mouse as a model organism.
12	Checkpoint-related syndromes	It is perhaps not surprising that genes involved in the DNA damage response and DNA repair are commonly mutated in incipient cancer cells on their road to malignancy. Defects in the ability to detect and repair mutations increase the likelihood of acquiring mutations that will ultimately help to fuel the runaway proliferation of cancer cells. Defects in checkpoint signaling are associated with a number of human diseases. Besides spontaneous mutations in checkpoint genes, familial syndromes have been identified in which specific checkpoint genes are mutated. During this session, two such syndromes will be discussed and compared.
13	Cancer treatment based on knowledge about the DNA damage response – targeted therapeutics	We will discuss two recent papers that make use of our increasing understanding of DNA damage signaling to derive new therapeutic strategies that specifically target cancer cells rather than healthy cells. We will learn about the concept of personalized cancer therapy.
14	Cancer treatment based on specific mutations that "drive" malignant growth – exploiting oncogene addiction	We will discuss two success stories of targeted anti-cancer therapy. Our knowledge about general principles of cancer cell proliferation will serve as a foundation to understand the mechanism of action of two recently developed anti-cancer therapeutics. We will discuss why these drugs specifically target cancer cells. Unfortunately, clinicians have seen the development of new resistance mechanisms that can abolish the beneficial effects of these drugs. We will discuss different resistance mechanisms and think about strategies that help to avoid the problem of resistance.