ABSTRACT
Bacterial abortive-infection systems limit the spread of foreign invaders by shutting down or killing infected cells before the invaders can replicate1,2. Several RNA-targeting CRISPR-Cas systems (that is, types III and VI) cause abortive-infection phenotypes by activating indiscriminate nucleases3-5. However, a CRISPR-mediated abortive mechanism that leverages indiscriminate DNase activity of an RNA-guided single-effector nuclease has yet to be observed. Here we report that RNA targeting by the type V single-effector nuclease Cas12a2 drives abortive infection through non-specific cleavage of double-stranded DNA (dsDNA). After recognizing an RNA target with an activating protospacer-flanking sequence, Cas12a2 efficiently degrades single-stranded RNA (ssRNA), single-stranded DNA (ssDNA) and dsDNA. Within cells, the activation of Cas12a2 induces an SOS DNA-damage response and impairs growth, preventing the dissemination of the invader. Finally, we harnessed the collateral activity of Cas12a2 for direct RNA detection, demonstrating that Cas12a2 can be repurposed as an RNA-guided RNA-targeting tool. These findings expand the known defensive abilities of CRISPR-Cas systems and create additional opportunities for CRISPR technologies.
Subject(s)
CRISPR-Associated Proteins , CRISPR-Cas Systems , DNA , RNA , CRISPR-Associated Proteins/metabolism , DNA/metabolism , DNA, Single-Stranded/metabolism , RNA/metabolism , SOS Response, Genetics , DNA Damage , RNA, Guide, CRISPR-Cas Systems , Gene EditingABSTRACT
THE BIG NATIONAL DATABASES AND STUDIES ON REAL WORLD DATA: EXAMPLE OF SARCOMAS IN FRANCE: Sarcomas are rare and heterogeneous tumours, and improvement of knowledge and of patient management need to gather and share data and biological material. The French sarcoma database stores in a warehouse clinical, pathological, molecular, therapeutic and follow-up data as well as data on samples and medical practices. This database and the national structured networks constitute major tools for the French Sarcoma Group.
Subject(s)
Databases, Factual , Sarcoma , Databases, Factual/statistics & numerical data , France , Humans , Sarcoma/genetics , Sarcoma/pathology , Sarcoma/therapyABSTRACT
BACKGROUND: Muir-Torre syndrome (MTS) is an autosomal dominant genodermatosis characterized by the association of at least 1 cutaneous sebaceous tumor and 1 internal malignancy, often arising in the gastrointestinal tract. It is secondary to germline mutations in DNA mismatch repair genes, mainly MLH-1 and MSH-2. OBSERVATIONS: We report the case of a 54-year-old man with a 2-year history of skin-colored papules clinically reminiscent of large sebaceous hyperplasias on the nose and back, but histologically diagnosed as sebaceous adenomas and epitheliomas. His family history was positive for colon cancer in the mother and 2 brothers. A colonoscopy done during the hospitalization revealed 2 sessile polyps in the left colon, both showing a low-grade dysplasia on the biopsy specimen. Immunohistochemical staining performed on the cutaneous and colic biopsy specimens revealed a lack of expression of MSH-2 and MSH-6. Genetic testing revealed microsatellite instability in the colon and cutaneous tumors. CONCLUSION: The immunohistochemical testing for MSH-2, MSH-6, and MLH-1 is useful for rapid identification of an underlying mismatch repair defect and early diagnosis of MTS.
