Essential Function of Dicer in Resolving DNA Damage in the Rapidly Dividing Cells of the Developing and Malignant Cerebellum

• Published in: Cell reports (Cambridge) Vol. 14; no. 2; pp. 216 - 224
• Main Authors: Swahari, Vijay, Nakamura, Ayumi, Baran-Gale, Jeanette, Garcia, Idoia, Crowther, Andrew J., Sons, Robert, Gershon, Timothy R., Hammond, Scott, Sethupathy, Praveen, Deshmukh, Mohanish
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.01.2016; Elsevier
• Subjects: Animals; apoptosis; Cell Proliferation; Cerebellum - cytology; Cerebellum - metabolism; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; dicer; DNA Damage; embryonic stem cells; medulloblastoma; Mice; Neural Stem Cells - physiology; p53; replicative stress; Ribonuclease III - genetics; Ribonuclease III - metabolism; dicer; apoptosis; medulloblastoma; embryonic stem cells; replicative stress; p53
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2015.12.037

Maintenance of genomic integrity is critical during neurodevelopment, particularly in rapidly dividing cerebellar granule neuronal precursors that experience constitutive replication-associated DNA damage. As Dicer was recently recognized to have an unexpected function in the DNA damage response, we examined whether Dicer was important for preserving genomic integrity in the developing brain. We report that deletion of Dicer in the developing mouse cerebellum resulted in the accumulation of DNA damage leading to cerebellar progenitor degeneration, which was rescued with p53 deficiency; deletion of DGCR8 also resulted in similar DNA damage and cerebellar degeneration. Dicer deficiency also resulted in DNA damage and death in other rapidly dividing cells including embryonic stem cells and the malignant cerebellar progenitors in a mouse model of medulloblastoma. Together, these results identify an essential function of Dicer in resolving the spontaneous DNA damage that occurs during the rapid proliferation of developmental progenitors and malignant cells. [Display omitted] •Dicer is highly expressed in rapidly proliferating cells (e.g., CGNPs and ESCs)•Dicer is essential for resolving replication-associated DNA damage in these cells•Degeneration seen with Dicer deficiency can be partially rescued by deletion of p53•Dicer deficiency induces DNA damage and reduces tumor burden in medulloblastomas Rapidly proliferating cells undergo replication-associated DNA damage. Swahari et al. use the developing cerebellum and embryonic stem cells to show that Dicer is critical for resolving endogenous DNA damage and preventing cell death. Medulloblastomas also rely on Dicer for survival, suggesting Dicer inhibitors could be developed as a potential therapy.