Abstract Protein-nucleic acid interactions are central to many biological processes. Our research is focused on two areas of protein-nucleic acid interactions: bacterial defense systems and translesion DNA synthesis (TLS). The studies on bacterial defense systems are an extension of our decades-long work on restriction-modification (R-M) systems. Over the past few years, many new bacterial defense systems have been discovered, and motivated by our success with R-M systems, we will undertake studies on two new systems: the cyclic oligonucleotide based anti- phage signaling system (CBASS) and a short prokaryotic Argonaute (pAgo) system. We will determine how these systems confer bacterial immunity; in particular, how they become allosterically activated for abortive infection - to prevent propagation of the invading DNA throughout the bacterial cell population. The studies on TLS are a continuation of our pioneering work on TLS polymerases and in understanding how cells cope with DNA damage. Recent advances in cryo-EM have allowed us to approach what seemed impossible at one-time, namely the structure of the complex multi-subunit TLS polymerase Polz. Polz stands out as the pivotal DNA polymerase in eukaryotes for maintaining genome integrity, and we will address how Polz works in conjunction with another polymerase Rev1 to extend DNA synthesis from DNA lesions. Together, these studies will set new paradigms in our understanding of bacterial immunity and in how eukaryotic cells cope with daily genotoxic stresses.