Accumulating evidence indicates that cryptochrome circadian regulatory (CRY) proteins have emerged as crucial regulators of osteogenic differentiation. However, the associated mechanisms are quite elusive. In this study, we show that knockdown of CRY2 downregulated the expression of runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), osteocalcin (OCN), and osteopontin (OPN) to facilitate osteoblast differentiation. Further study identified that CRY2 was directly targeted by microRNA (miR)-7-5p, which was highly induced during osteoblast differentiation. The expression of Runx2, ALP, collagen type I alpha 1 (Col1a1), and OCN was upregulated by overexpression of miR-7-5p and induction of osteoblast differentiation. Moreover, signal transducer and activator of transcription 3 (STAT3) transcriptionally activated miR-7-5p to significantly enhance the expression of above osteogenic marker genes and mineral formation. However, overexpression of CRY2 abolished the osteogenic differentiation induced by miR-7-5p overexpression. Silencing of CRY2 unraveled the binding of CRY2 with the circadian locomotor output cycles kaput (CLOCK)/brain and muscle ARNT-like 1 (BMAL1) complex to release CLOCK/BMAL1, which facilitated the binding of CLOCK/BMAL1 to the promoter region of the P300 E-box to stimulate the transcription of P300. P300 subsequently promoted the acetylation of histone 3 and the formation of a transcriptional complex with Runx2 to enhance osteogenesis. Taken together, our study revealed that CRY2 is repressed by STAT3/miR-7-5p to promote osteogenic differentiation through CLOCK/BMAL1/P300 signaling. The involved molecules may be potentially targeted for treatment of osteoporosis.

HORMAD1 is a meiosis-specific protein that promotes synapsis and recombination of homologous chromosomes in meiotic prophase. Originally identified as a cancer/testis antigen, HORMAD1 is also aberrantly expressed in several cancers. However, the functions of HORMAD1 in cancer cells are still not clear. Here, we show that HORMAD1 is aberrantly expressed in a wide variety of cancers and compromises DNA mismatch repair in cancer cells. Mechanistically, HORMAD1 interacts with MCM8–MCM9 complex and prevents its efficient nuclear localization. As a consequence, HORMAD1-expressing cancer cells have reduced MLH1 chromatin binding and DNA mismatch repair defects. Consistently, HORMAD1 expression is associated with increased mutation load and genomic instability in many cancers. Taken together, our study provides mechanistic insights into HORMAD1’s functions in cancer cells, which can potentially be exploited for targeted therapy of HORMAD1-expressing cancers.

DNA double-strand breaks (DSBs) pose a serious threat to genomic stability. Paradoxically, hundreds of programed DSBs are generated by SPO11 in meiotic prophase, which are exclusively repaired by homologous recombination (HR) to promote obligate crossover between homologous chromosomes. In somatic cells, MRE11-RAD50-NBS1 (MRN) complex-dependent DNA end resection is a prerequisite for HR repair, especially for DSBs that are covalently linked with proteins or chemicals. Interestingly, all meiotic DSBs are linked with SPO11 after being generated. Although MRN complex's function in meiotic DSB repair has been established in lower organisms, the role of MRN complex in mammalian meiotic DSB repair is not clear. Here, we show that MRN complex is essential for repairing meiotic SPO11-linked DSBs in male mice. In male germ cells, conditional inactivation of NBS1, a key component of MRN complex, causes dramatic reduction of DNA end resection and defective HR repair in meiotic prophase. NBS1 loss severely disrupts chromosome synapsis, generates abnormal chromosome structures, and eventually leads to meiotic arrest and male infertility in mice. Unlike in somatic cells, the recruitment of NBS1 to SPO11-linked DSB sites is MDC1-independent but requires other phosphorylated proteins. Collectively, our study not only reveals the significance of MRN complex in repairing meiotic DSBs but also discovers a unique mechanism that recruits MRN complex to SPO11-linked DSB sites.

Summary Wintersweet (Chimonanthus praecox) is one of the most important ornamental plants. Its color is mainly determined by the middle tepals. However, the molecular mechanisms underlying the intriguing flower color development among different wintersweet groups are still largely unknown. In addition, wintersweet belongs to magnoliids, and the phylogenetic position of magnoliids remains to be determined conclusively. Here, the whole genome of red flower wintersweet, a new wintersweet type, was sequenced and assembled with high quality. The genome comprised 11 super‐scaffolds (chromosomes) with a total size of 737.03 Mb. Based on the analyses of the long branch attraction, incomplete lineage sorting, sparse taxon sampling, and other factors, we suggest that a bifurcating tree may not fully represent the complex early diversification of the angiosperms and that magnoliids are most likely sister to the eudicots. The wintersweet genome appears to have undergone two whole‐genome duplication (WGD) events: a recent WGD event representing an independent event specific to the Calycanthaceae and an ancient WGD event shared by Laurales. By integrating genomic, transcriptomic, and metabolomic data, CpANS1 and the transcription factor CpMYB1 were found to play key roles in regulating tepal color development, whereas CpMYB1 needs to form a complex with bHLH and WD40 to fully perform its regulatory function. The present study not only provides novel insights into the evolution of magnoliids and the molecular mechanism for flower color development, but also lays the foundation for subsequent functional genomics study and molecular breeding of wintersweet.