Understanding and targeting RNA/transcription-dependent DNA repair in cancer cells

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Project Summary/Abstract Genomic instability is a hallmark of cancer and is an enabling characteristic of tumorigenesis. Genomic instability can arise from deficiency in DNA repair system. On one hand, deficiency in DNA repair system leads to increased mutation rate in the entire genome, results in genomic instability. On the other hand, deficiency in certain DNA repair pathway(s) may render the cell highly dependent on other repair pathway(s) to cope with high mutation burden, which may constitute a vulnerability that can be exploited for targeted therapies in cancer. Recent success of the PARP inhibitors for treatment of BRCA mutation cancers, has demonstrated great potential to exploit cancer cell-specific dependency on certain DNA repair pathways for cancer therapies. In addition to cancer with BRCA deficiency, multiple researches have suggested to expand PARP inhibitor treatment to cancers with deficiency in homologous recombination (HR) DNA repair pathways. However, our understanding of the HR DNA repair pathways is quite limited. In our recent study on HR DNA repair, we have discovered a novel RNA-dependent HR DNA repair pathway, which is controlled by the DNA repair protein RAD51AP1. The unique ability of RAD51AP1 to promote HR in transcribed regions makes it an attractive target to specifically exacerbate the DNA damage in active genes in cancer cells, especially in cancers driven by oncogenic transcription factors or epigenetic regulators. The amplification and up-regulation of RAD51AP1 in multiple types of cancer have led us to hypothesize that RAD51AP1 may be indispensable in cancer cells with high levels of transcription-driven DNA damage and defects in the canonical HR pathway, which could be exploited for therapeutic interventions. Importantly, the function of RAD51AP1 in promoting HR repair depends on its R-loop formation activity via its DNA/RNA binding motif. This binding interface could potentially provide a targetable site for small molecules to disrupt RAD51AP1 binding to DNA/RNA, which may effectively abolish its R-loop formation activity and results in attenuating its HR DNA repair function in the cell. In summary, we want to expand our mechanistic understanding of the novel RNA/transcription-dependent HR DNA repair pathway, investigate the role of this novel DNA repair in specific types of cancer, ultimately, exploit cancer cell-specific dependency of this pathway for potential cancer therapies.