Breaking News: Unraveling Responses to DNA damage
Genetic factors and errors in cell development play a prominent role in childhood cancers.
During development of the immune system, lymphocyte cells must create intentional breaks in DNA in order to create a diverse immune system.
Improper handling of these breaks can lead to genetic changes that can cause leukemias and lymphomas.
DNA (Deoxyribonucleic Acid) has become the poster child for biology. The familiar double helix has even appeared in sculptures, jewelry, and as playground equipment. It is, after all, a good looking molecule.
While often portrayed as the bedrock of being, the truth is that DNA is not all that solid and stable. Made up of hundreds of millions of smaller units held together by chemical bonds, DNA is highly reactive and vulnerable to breakage from not only the usual toxic suspects—smoking and radiation— but from normal cell processes as well.
In fact, immune cells known as lymphocytes (a type of white blood cell in the human immune system) deliberately break their own DNA. This enables the cells to remix and splice together pieces of DNA in new ways. It is how lymphocytes create new antibodies that can recognize the billions of different foreign substances that may enter the body.
DNA breaks in all types of cells activate a “damage response system,” a complex network of integrated molecular pathways that either strive to repair the DNA, cause the cell to stop dividing, or cause the cell to self-destruct. These systems, when functioning properly, prevent cells from becoming cancerous.
“Lymphocytes are of particular interest because breakdowns in these cells’ DNA damage response systems can corrupt immune development or lead to leukemias and lymphomas,” says Jeff Bednarski, MD, PhD, a Children’s Discovery Institute Fellow. Dr. Bednarski’s mentor is Barry Sleckman, MD, PhD, who directs the Division of Laboratory and Genomic Medicine.
“A good outcome for a lymphocyte cell depends on the successful recombination (joining) of two distant DNA segments, such that the cell generates an antigen receptor and continues development,” said Dr. Bednarski.
“Abnormal joining can result in the development of tumors unless other signals direct the cell to self-destruct.
My research focuses on how intentional DNA breaks in lymphocytes interact with these traditional cell differentiation signals and pathways.” In his research, Dr. Bednarski introduces double stranded DNA breaks in cultured lymphocyte cells in order to study the genes that are turned on as a result of the damage and their interactions with other damage response systems.
An enormous amount of work remains to fully understand and define the cellular intricacies that lead to such radically different outcomes for cells following DNA breaks. Dr. Bednarski’s work will contribute new insights into the development of leukemias and lymphomas, and new ideas about the impact of chemotherapy on immune function.