Current Research and Scholarly Interests
We are a functional genomics laboratory interested in elucidating mechanisms of DNA repair pathway choice and genome instability. We use genome-wide repair fate maps of targeted DNA double strand breaks (DSBs) to develop pathway-specific models and combinatorial therapies. Our expertise overlaps many different fields including: genome editing, ionizing radiation, cancer therapeutics, V(D)J and IgH class switch recombination, repair during transcription and replication, and meiosis.
We are specifically interested in secondary repair mechanisms, their collaboration with the epigenetic DNA Damage Response (DDR), and how they can be promoted over nonhomologous end joining (NHEJ) or homologous recombination (HR) in cancers.
Our recent work in quiescent cells revealed a robust bona fide alternative end joining (A-EJ) mechanism, completely independent of NHEJ, comprising the Parp1-XRCC1/Lig III axis and dependent on 53BP1 and the ATM-initiated DDR. This pathway is distinguished from an NHEJ-variant A-EJ mechanism we describe that leverages the first half of NHEJ (i.e. DNA-PK) to resect ends and form joints that are enriched with microhomology. Curiously, these activities do not require polymerase theta, suggesting additional mechanisms that leverage microhomology-mediated end-joining (MMEJ) may contribute to the COSMIC (v3.4) indel ID6 and ID8 signatures found in many cancer genomes.