Search

An ideal cancer therapeutic strategy involves the selective killing of cancer cells without affecting the surrounding normal cells. However, researchers have failed to develop such methods for achieving selective cancer cell death because of shared features between cancerous and normal cells. In this study, we have developed a therapeutic strategy called the cancer-specific insertions-deletions (InDels) attacker (CINDELA) to selectively induce cancer cell death using the CRISPR-Cas system. CINDELA utilizes a previously unexplored idea of introducing CRISPR-mediated DNA double-strand breaks (DSBs) in a cancer-specific fashion to facilitate specific cell death. In particular, CINDELA targets multiple InDels with CRISPR-Cas9 to produce many DNA DSBs that result in cancer-specific cell death. As a proof of concept, we demonstrate here that CINDELA selectively kills human cancer cell lines, xenograft human tumors in mice, patient-derived glioblastoma, and lung patient-driven xenograft tumors without affecting healthy human cells or altering mouse growth.

Significance Transcription of ribosomal RNA (rRNA), which composes the ribosome with other proteins, is tightly regulated to maintain the right number of ribosomes. Many DNA repair proteins have functions in addition to their role in DNA repair. We provide evidence that SHPRH functioning in DNA repair at stalled DNA replication forks recognizes epigenetic histone codes of rDNA through its plant homeodomain (PHD) and modulates 47S rRNA transcription. SHPRH bound to rDNA promoters and promoted RNA polymerase I recruitment for rRNA transcription. SHPRH localization to the rDNA promoter was inhibited by trimethylation of histone H3 lysine 4, which is a mark of the rDNA promoter at poised status on starvation. Collectively, we suggest a mechanism controlling 47S rRNA transcription by SHPRH in a histone methylation-dependent manner.