Anti-Cancer Drugs Effect on Quasi-palindrome Mutations in Escherichia coli

Abstract

Cancer is one of the world's largest health problems in today’s age. The Global Burden of Disease estimates that 10 million people died as a result of cancer per year (IHME). Although there are many treatments for different types of cancer, many of the drugs used are known to have severe side effects. These known consequences include hair loss, nausea, and, unfortunately, an increase in DNA mutation, which can trigger other classes of diseases. One class of mutations that have been studied and linked to a form of cancer is Quasi-palindrome template switch mutations. Quasi-palindromes are nearly perfect inverted repeats of nucleotides able to form DNA secondary structures. These Hairpins are an example of a secondary DNA structure made by DNA repeats and are known to block the DNA replication fork (VOINEAGU et al. 2008). Once DNA replication is blocked by these secondary DNA structures, the DNA replication fork needs to find a solution to continue the replication process. At some frequency, DNA polymerase (responsible for replicating the DNA) can use alternative DNA strands as templates to make more DNA. One alternative method is called “Template-switching”, and it results in a mutation that creates a perfect palindrome from a quasi-palindromic sequence. Previous work has linked anti-cancer drugs such as 5-azacytidine to an increase of QP mutations (Laranjo 2018). Therefore, I am interested in analyzing other anti-cancer drugs and their potential to cause QP mutations. Using an FDA approved drug library, with over 300 different drugs, we will select anti-cancer drugs to screen for QP mutators. We have constructed a QP reporter in E. coli that is specific for QP mutations (Laranjo 2017). To understand the effect of anti-cancer drugs during DNA replication is critical to give us an understanding of potential side effects for patients undergoing chemotherapy.