Courses:

7.03 Genetics
7.05 General Biochemistry
7.06 Cell Biology
or
7.28 Molecular Biology

The DNA contained in human cells is under constant attack by both exogenous and endogenous agents that can damage one of its three billion base pairs. To cope with this permanent exposure to DNA-damaging agents, such as the sun's radiation or by-products of our normal metabolism, powerful DNA damage checkpoints have evolved that allow organisms to survive this constant assault on their genomes. The tremendous importance of checkpoints is underlined by the fact that defects in checkpoint genes are commonly seen in cancer. Once DNA damage checkpoints detect DNA lesions, cellular proliferation is stopped immediately and DNA repair is initiated. If the extent of damage is beyond the capacity of the cell's repair systems, checkpoint signaling ensures elimination of such damaged cells by the induction of a cellular suicide program known as programmed cell death, or apoptosis. Cellular responses to DNA damage constitute one of the most important fields in cancer biology. Exciting work in this area has taught us important lessons, such as: DNA damage can cause cancer; paradoxically, the induction of DNA damage is the mechanism of action of the major approaches to treating cancer (radiation and chemotherapy); and DNA damage of normal tissues is responsible for most of the side effects of cancer therapy, such as hair loss. We will analyze classical and recent papers from the primary research literature to gain a profound understanding of checkpoints that act as powerful emergency brakes to prevent cancer. We will consider basic principles of cell proliferation and molecular details of the DNA damage response. We will discuss the methods and model organisms typically used in this field as well as how an understanding of checkpoint mechanisms translates into the development of treatments for human cancer. This course will not stop at discussing literature. We will take it one step further and analyze real data in an MIT Biology laboratory.

One primary objective of this course is to introduce students into the analysis of primary research literature. To achieve this, we will have weekly sessions, during which we will discuss in detail two scientific papers (both classic and recent breakthrough papers). With the exception of the first meeting, no formal lectures will be given. Instead, course participants will actively present as well as drive the discussions of the papers.

The second objective of this course is to gain a deeper understanding of the response mechanisms a cell puts into place when it faces DNA damage. We will learn that these defense mechanisms are crucial for cellular survival and that misregulation of these processes can lead not only to cell death but also to catastrophic diseases, such as cancer. The cellular mechanisms involved in the so-called DNA damage response are well studied both at the organism level as well as at the molecular level. We will see that the core machinery of the DNA damage response consists of a highly specialized network of protein kinases and phosphatases, which are rapidly acting enzymes that can add or remove phosphates to substrates. The general principles of the DNA damage response are applicable to a wider range of stress response programs commonly used by cells. We will see that there is some overlap between general stress response pathways and the highly specialized DNA damage response.

This course is graded pass/fail. The grading will be based on participation during presentations and discussions as well as on two assignments. Attendance at all meetings is very important. If an absence is unavoidable, instructors should be notified in advance and make-up work will be assigned.