Summary In lower eukaryotes, Sir2 serves as a histone deacetylase and is implicated in chromatin silencing, longevity and genome stability. Here we mutated the SIRT1 gene, a homolog of yeast Sir2, in mice to study its function. We showed that a majority of SIRT1-null embryos died between E9.5–E14.5, displaying altered histone modification, impaired DNA damage response, and reduced ability to repair DNA damage. We demonstrated that SIRT1+/−;p53+/− mice developed tumors in multiple tissues, whereas activation of SIRT1 by resveratrol treatment reduced tumorigenesis. Finally, we showed that many human cancers exhibited reduced level of SIRT1 than their normal controls. Thus, SIRT1 acts as a tumor suppressor through its role in DNA damage response, genome integrity, and tumor suppression. Significance SIRT1 has diverse roles in various biological processes, including caloric restriction that causes changes in glucose metabolism and lifespan. The role of SIRT1 in cancer is currently under debate due to some recent different findings. It is known that calorie restriction, which activates SIRT1, extends lifespan and inhibits tumorigenesis. On the other hand, SIRT1 deacetylates p53 to decrease its activity. It was therefore hypothesized increased SIRT1 activity, although it extends lifespan, may elevate cancer risk. Here we demonstrate SIRT1 plays an important role in DNA damage response and genome integrity by maintaining proper chromatin structure and DNA damage repair foci formation. We further show that SIRT1 serves as a tumor suppressor in mice and in some types of human cancers.

Abstract We first described the 2019 novel coronavirus infection in 10 children occurring in areas other than Wuhan. The coronavirus diseases in children are usually mild and epidemiological exposure is a key clue to recognize pediatric case. Prolonged virus shedding is observed in respiratory tract and feces at the convalescent stage.

Tumor cells display a different profile of gene expression than their normal counterparts. Perturbations in the levels of cellular splicing factors can alter gene expression, potentially leading to tumorigenesis. We found that splicing factor SRp20 (SFRS3) is highly expressed in cancers. SRp20 regulated the expression of Forkhead box transcription factor M1 (FoxM1) and two of its transcriptional targets, PLK1 and Cdc25B, and controlled cell cycle progression and proliferation. Cancer cells with RNAi-mediated reduction of SRp20 expression exhibited G2/M arrest, growth retardation, and apoptosis. Increased SRp20 expression in rodent fibroblasts promoted immortal cell growth and transformation. More importantly, we found that SRp20 promoted tumor induction and the maintenance of tumor growth in nude mice and rendered immortal rodent fibroblasts tumorigenic. Collectively, these results suggest that increased SRp20 expression in tumor cells is a critical step for tumor initiation, progression, and maintenance.

Box C/D RNA protein complexes (RNPs) direct site-specific 2'-O-methylation of RNA and ribosome assembly. The guide RNA in C/D RNP forms base pairs with complementary substrates and selects the modification site using a molecular ruler. Despite many studies of C/D RNP structure, the fundamental questions of how C/D RNAs assemble into RNPs and how they guide modification remain unresolved. Here we report the crystal structure of an entire catalytically active archaeal C/D RNP consisting of a bipartite C/D RNA associated with two substrates and two copies each of Nop5, L7Ae and fibrillarin at 3.15-Å resolution. The substrate pairs with the second through the eleventh nucleotide of the 12-nucleotide guide, and the resultant duplex is bracketed in a channel with flexible ends. The methyltransferase fibrillarin binds to an undistorted A-form structure of the guide-substrate duplex and specifically loads the target ribose into the active site. Because interaction with the RNA duplex alone does not determine the site specificity, fibrillarin is further positioned by non-specific and specific protein interactions. Compared with the structure of the inactive C/D RNP, extensive domain movements are induced by substrate loading. Our results reveal the organization of a monomeric C/D RNP and the mechanism underlying its site-specific methylation activity.