Disrupted-in-schizophrenia 1 (DISC1) has emerged as a schizophrenia-susceptibility gene affecting various neuronal functions. In this study, we characterized Mitofilin, a mitochondrial inner membrane protein, as a mediator of the mitochondrial function of DISC1. A fraction of DISC1 was localized to the inside of mitochondria and directly interacts with Mitofilin. A reduction in DISC1 function induced mitochondrial dysfunction, evidenced by decreased mitochondrial NADH dehydrogenase activities, reduced cellular ATP contents, and perturbed mitochondrial Ca 2+ dynamics. In addition, deficiencies in DISC1 and Mitofilin induced a reduction in mitochondrial monoamine oxidase-A activity. The mitochondrial dysfunctions evoked by the deficiency of DISC1 were partially phenocopied by an overexpression of truncated DISC1 that is associated with schizophrenia in human. DISC1 deficiencies induced the ubiquitination of Mitofilin, suggesting that DISC1 is critical for the stability of Mitofilin. Finally, the mitochondrial dysfunction induced by DISC1 deficiency was partially reversed by coexpression of Mitofilin, confirming a functional link between DISC1 and Mitofilin for the normal mitochondrial function. According to these results, we propose that DISC1 plays essential roles for mitochondrial function in collaboration with a mitochondrial interacting partner, Mitofilin.IMMT | mitochondrial dysfunctions | hyperdopaminergia | calcium buffering | psychiatric disorders

Cyclin‐dependent kinase 12 (CDK12) has emerged as an effective therapeutic target due to its ability to regulate DNA damage repair in human cancers, but little is known about the role of CDK12 in driving tumorigenesis. Here, we demonstrate that CDK12 promotes tumor initiation as a novel regulator of cancer stem cells (CSCs) and induces anti‐HER2 therapy resistance in human breast cancer. High CDK12 expression caused by concurrent amplification of CDK12 and HER2 in breast cancer patients is associated with disease recurrence and poor survival. CDK12 induces self‐renewal of breast CSCs and in vivo tumor‐initiating ability, and also reduces susceptibility to trastuzumab. Furthermore, CDK12 kinase activity inhibition facilitates anticancer efficacy of trastuzumab in HER2+ tumors, and mice bearing trastuzumab‐resistant HER2+ tumor show sensitivity to an inhibitor of CDK12. Mechanistically, the catalytic activity of CDK12 is required for the expression of genes involved in the activation of ErbB‐PI3K‐AKT or WNT‐signaling cascades. These results suggest that CDK12 is a major oncogenic driver and an actionable target for HER2+ breast cancer to replace or augment current anti‐HER2 therapies.

Background: Cdk5 is a kinase involved in the various neuronal processes. Results: Cdk5 directly phosphorylates CLOCK and regulates its transcriptional activity in association with altered stability and subcellular distribution. Conclusion: Cdk5 functions as a regulator of CLOCK protein.Significance: Our findings may provide mechanistic links between diverse Cdk5-mediated brain functions and the molecular clock.

Histone methyltransferase NSD3 is frequently dysregulated in human cancers, yet the epigenetic role of NSD3 during cancer development remains elusive. Here we report that NSD3-induced methylation of H3K36 is crucial for breast tumor initiation and metastasis. In patients with breast cancer, elevated expression of NSD3 was associated with recurrence, distant metastasis, and poor survival. In vivo, NSD3 promoted malignant transformation of mammary epithelial cells, a function comparable to that of HRAS. Furthermore, NSD3 expanded breast cancerinitiating cells and promoted epithelial-mesenchymal transition to trigger tumor invasion and metastasis. Mechanistically, the long isoform (full-length transcript) of NSD3, but not its shorter isoform lacking a catalytic domain, cooperated with EZH2 and RNA polymerase II to stimulate H3K36me2/3-depen-dent transactivation of genes associated with NOTCH receptor cleavage, leading to nuclear accumulation of NICD and NICDmediated transcriptional repression of E-cadherin. Furthermore, mice harboring primary and metastatic breast tumors with overexpressed NSD3 showed sensitivity to NOTCH inhibition. Together, our findings uncover the critical epigenetic role of NSD3 in the modulation of NOTCH-dependent breast tumor progression, providing a rationale for targeting the NSD3-NOTCH signaling regulatory axis in aggressive breast cancer.Significance: This study demonstrates the functional significance of histone methyltransferase NSD3 in epigenetic regulation of breast cancer stemness, EMT, and metastasis, suggesting NSD3 as an actionable therapeutic target in metastatic breast cancer.

Many DNA repair proteins have additional functions other than their roles in DNA repair. In addition to catalyzing PCNA polyubiquitylation in response to the stalling of DNA replication, SHPRH has the additional function of facilitating rRNA transcription by localizing to the ribosomal DNA (rDNA) promoter in the nucleoli. SHPRH was recruited to the rDNA promoter using its plant homeodomain (PHD), which interacts with histone H3 when the fourth lysine of H3 is not trimethylated. SHPRH enrichment at the rDNA promoter was inhibited by cell starvation, by treatment with actinomycin D or rapamycin, or by depletion of CHD4. SHPRH also physically interacted with the RNA polymerase I complex. Taken together, we provide evidence that SHPRH functions in rRNA transcription through its interaction with histone H3 in a mammalian target of rapamycin (mTOR)-dependent manner.SHPRH | rRNA transcription | histone H3 methylation | mTOR H uman ribosomal DNA (rDNA) is composed of hundreds of tandem repeats of 42.9-kb rDNA units that are organized into transcribed and intergenic regions (1). About one-half the 47S precursor ribosomal RNA (pre-rRNA) genes are actively transcribed, and the other half remain silent (2, 3). Transcription, processing of rRNA, and the assembly of ribosomes take place in the nucleoli (2, 4). Once transcribed in the nucleoli, pre-rRNA is immediately processed into small mature 28S, 18S, and 5.8S rRNAs that, together with ribosomal proteins, make a ribosome. Tight regulation of ribosome biogenesis, including rRNA transcription and synthesis of ribosomal proteins, is important in many biological processes such as cell proliferation, apoptosis, and autophagy (5-7), and is closely associated with metabolic processes. Because of its importance in many metabolic pathways, dysregulation of ribosomal biogenesis is linked to aging and diverse diseases, including anemia and cancers (8-12). 47S pre-rRNA is transcribed by the RNA polymerase I complex, whose activity is controlled by cellular responses to nutritional states, cellular stresses, growth, differentiation, and cell cycle (9). Posttranslational modifications of transcription factors, for example, phosphorylation of upstream binding factor (UBF), help regulate rRNA transcription (13). In addition to posttranslational modifications of transcription factors, nucleolar remodeling complex, NuRD (nucleosome remodeling and deacetylation) complex, and energy-dependent nucleolar silencing complex also affect rRNA transcription by modifying epigenetic signatures of rDNA, as well as histones in the rDNA promoter (14-16). In addition to conventional active and silent histone signatures, the rDNA promoter has another histone signature called a poised state. CHD4 and CSB-containing NuRD complex establish a poised chromatin signature of rDNA that represses but primes rRNA transcription by marking histone H3 with both active (H3 K4me3) and inactive (H3 K27me3) modifications (16). However, it is unclear how these epigenetic changes control the transcription of rRNA.The mammali...