Research

MMEJ is an intrinsically mutagenic repair pathway driven by DNA polymerase theta (Polθ, POLQ), characterized by microhomology, insertions and deletions that scar the repair sites. A mutational signature associated with MMEJ, has been identified across different species, as well as in cancer. Why this inherently mutagenic pathway has been evolutionarily conserved is yet to be understood. When the canonical DSBs repair pathway, NHEJ and HR, are inactivated, cells rely on MMEJ for survival. Targeting this pathway has emerged as a promising therapeutic approach for cancer patients with defective HR. 

We recently discovered that MMEJ is the primary DSB repair pathway during mitosis, where HR and NHEJ are inactivated, challenging the classical view of MMEJ as a backup. In the lab we aim to define and mechanistically characterize MMEJ's role in mitosis and its impact on genome diversity. 

Although a significant portion of our genome is transcribed, DSB repair pathways have traditionally been viewed as separate from RNA transcripts. However, emerging evidence suggests that RNA:DNA hybrids and transcripts near damaged sites can indirectly influence repair outcomes. We recently showed that in human cells RNA-containing donors and mRNA serve as templates for DSB repair, offering an error-free repair mechanism at transcribed regions. Our findings identified DNA polymerase zeta (Polζ, REV3L) as a potential reverse transcriptase facilitating RNA-templated DSB repair (RT-DSBR). Notably, we discovered that when breaks occur within introns and are repaired using spliced mRNA, the process leads to precise intron deletion, leaving a distinct genomic scar—a signature observed in cancer genomes. In the lab, we aim to uncover the mechanistic basis of RT-DSBR and test the hypothesis that in non-dividing cells, where HR is suppressed, RNA-templated repair may have evolved as an alternative strategy for maintaining genome stability.