Research

DNA DAMAGE AND REPAIR

Figure 1: Overview of the types and causes of DNA damage. Cells have evolved a variety of pathways that repair DNA. Image made in part with BioRender.

Cancer is fundamentally a disease of DNA. Damage to DNA during replication can lead to mutations, which, when they accumulate, can cause diseases, most notably cancer. Cells have various proteins that protect the genome by detecting and repairing DNA damage (Figure 1). However, when these protective proteins are defective, mutations can accumulate, leading to cancer. Our research focuses on uncovering the mechanisms by which DNA repair proteins function. By combining biochemistry, chemistry, molecular biology, and genetics, we aim to understand this diverse family of proteins better and identify new diagnostic methods and therapeutic targets. Check out our Publications page to see our work!

DNA MISMATCH REPAIR

(eukaryotic)

Figure 2: (A) Mismatch repair is a spellchecking system for DNA and repairs mispaired nucleic acid bases. If left unrepaired, mispairs can become mutations, which can potentially lead to disease. The mismatch repair pathway requires protein factors to detect the mispaired bases, and the actions of the MutL𝛼 nuclease to start the repair process. Several projects in the lab investigate how the MutL𝛼 protein starts this repair process. (B) We found that MutL𝛼 reshapes higher-ordered DNA structure as part of its activation mechanism. See Witte, et al., under Publications. (C) We also found that MutL𝛼 protects breaks on newly replicated DNA that act as markers or signposts for which strand needs to be repaired to prevent the formation of mutations. See Piscitelli, et al., under Publications.

DNA mismatch repair functions as a spellchecking mechanism that scans for errors in DNA, known as mismatches, which can lead to mutations. Defects in mismatch repair proteins are linked to Lynch syndrome, a hereditary cancer syndrome affecting approximately 1 in 300 individuals. However, about 95% of those with Lynch syndrome are unaware of their condition. Lynch syndrome increases the lifetime risk and potential for early onset of various cancers, including colorectal and endometrial cancers (Lynch et al., 2015, Nat. Rev. Cancer, 15, 181–194).

Our lab investigates how mismatch repair proteins efficiently detect and correct these DNA errors and how defects in these mechanisms contribute to human cancers (Manhart, 2021, Encyclopedia of Biological Chemistry, 3rd edition) (Figure 2). Understanding these mechanisms can improve diagnosis and reveal new therapeutic targets.

In addition to its role in DNA spellchecking, mismatch repair is also involved in the expansion of trinucleotide repeats in the genome. These expansions are associated with over 30 neurological disorders, including Huntington's disease, as well as with various cancers and other diseases related to genome instability. Our research into DNA mismatch repair proteins also aims to explore their involvement in diseases linked to trinucleotide repeat expansions.

DOUBLE STRAND BREAK REPAIR

(eukaryotic)

Figure 3: DNA double strand breaks can be repaired by a pathway called "homologous recombination." (A) In meiosis, MutL family proteins repair double strand breaks by homologous recombination. Without these proteins, the risk of infertility increases. (B) We found that MutL family proteins hold two DNA molecules in close proximity and this activity is needed for DNA repair. The broken DNA in double strand break repair is repaired using a second DNA molecule (See Witte, et al., under Publications). Our data suggest how MutL family proteins promote double strand break repair by homologous recombination.

DNA recombination is a specialized form of DNA double-strand break repair in which the break is repaired using sequence information from homologous DNA, such as the sister chromosome or exogenous DNA. This process is employed by all organisms to repair DNA, and can lead to the exchange of DNA between fragments, contributing to genetic diversity—bacteria, for example, can acquire antibiotic resistance through this process.

Most organisms use DNA mismatch repair proteins to mediate DNA recombination. However, the specific ways in which these proteins function in recombination, utilizing properties and mechanisms similar to those involved in DNA mismatch repair, remain unclear (Manhart and Alani, 2016, DNA Repair, 38, 84-93).

Our lab employs a range of techniques, including biochemistry, chemistry, biophysics, molecular biology, and genetics, to elucidate how DNA recombination operates. By uncovering these mechanisms, we aim to improve the diagnosis of diseases linked to dysregulated genetic recombination, understand the origins of antibiotic resistance in bacteria, and identify new therapeutic targets.

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