Syllabus

Course Meeting Times

Lectures: 1 session / week, 2 hours / session

Prerequisites

Recommended prerequisites are:

7.03 Genetics

7.05 General Biochemistry

7.06 Cell Biology

7.28 Molecular Biology

Course Description

A never-ending molecular war takes place in the nucleus of your cells, with DNA damage occurring at a rate of over 20,000 lesions per cell per day. Where does this damage come from, and what are its consequences? What are the differences in the molecular blueprint between individuals who can sustain attacks on DNA and remain healthy compared to those who become sick? Constant exposure to exogenous factors commonly found in food, water, air, and tobacco smoke as well as endogenous byproducts of metabolism can damage DNA. If left unrepaired, this damage can lead to various disorders, such as diabetes, premature aging, neurodegenerative disorders, and cancer. To preserve the integrity of the genome, our cells have evolved an elegant collaboration among multiple DNA repair pathways, which respond to specific DNA lesions, and checkpoints, which arrest the cell cycle to allow additional time for repair to proceed or to stimulate programmed cell death if the damage is too extensive. An individual's distinct genetic background influences the susceptibility of his or her cells to particular types of damage and their ability to process specific lesions.

These differences can influence how cells from healthy individuals respond to damaging agents, which in turn can cause one individual to be more sensitive to a particular form of DNA damage than another. Thus, exposure to genotoxins that damage DNA, like the alkylating agent mustard gas, is dangerous because it can increase the susceptibility of cells to acquiring mutations that contribute to carcinogenesis and death. Counterintuitively, closely related chemicals like carmustine (also known as BCNU) are components of drug combinations used to treat cancer, and so genetic differences among individuals that influence pathways involved in the repair of DNA damage can play a role in responses to chemotherapeutic treatments. Additionally, individuals who harbor defects in a DNA repair pathway are generally more sensitive to the effects of DNA damage and are at an elevated risk of disease.

This course will survey the primary research literature concerning fundamental DNA damage repair pathways, including mismatch repair, direct reversal, nucleotide excision repair, base excision repair, and double strand break repair. We will explore the major sources of both nuclear and mitochondrial DNA damage and how mutations that cause imbalances in repair proteins can lead to diseases, including breast, colon and brain cancers; neurological disorders like ataxia telangiectasia and Alpers' disease; and premature aging disorders like Werner's syndrome and xeroderma pigmentosum. We will discuss how an understanding of DNA repair pathways can be utilized in the prevention and management of these diseases. We will consider how different model systems (including yeast, mice, and human cells) are studied in the laboratory to answer fundamental questions concerning DNA damage and genomic instability. We will learn how to critically evaluate the primary scientific literature, with an emphasis on experimental design and the presentation and interpretation of results. Students will have the opportunity to visit a research facility and to attend research seminars, including the DNA Repair and Mutagenesis seminar series, and in this way meet local scientists in the DNA repair field.

Format

This course will have a discussion format and will be graded pass / fail. Grading will be based on student attendance, participation in discussions, completion of short weekly assignments, a mid-term writing assignment, and an oral presentation. Students must prepare for each meeting by reading the assignments. At the end of each session, the instructors will provide a brief introduction of the topics that will be covered in the following week.

Goals

This course will introduce students to key strategies that the cell uses to repair damaged DNA upon exposure to exogenous and endogenous genotoxic factors. This overview of DNA repair strategies will include: mismatch repair, direct reversal, nucleotide excision repair, base excision repair, and double strand break repair. In addition to exploring the general mechanisms by which cells repair DNA damage, the course will also explore how these DNA repair strategies operate differently in mitochondria and stem cells. We will discuss how variability in DNA repair capacity exists among individuals and among tissues, and the consequences of such variability for susceptibility to disease and treatment.

Calendar