The mechanism by which the 8q24 MYC enhancer region, including cancer-associated variant rs6983267, increases cancer risk is unknown due to the lack of protein-coding genes at 8q24.21. Here we report the identification of long noncoding RNAs named cancer-associated region long noncoding RNAs (CARLos) in the 8q24 region. The expression of one of the long noncoding RNAs, CARLo-5, is significantly correlated with the rs6983267 allele associated with increased cancer susceptibility. We also found the MYC enhancer region physically interacts with the active regulatory region of the CARLo-5 promoter, suggesting long-range interaction of MYC enhancer with the CARLo-5 promoter regulates CARLo-5 expression. Finally, we demonstrate that CARLo-5 has a function in cell-cycle regulation and tumor development. Overall, our data provide a key of the mystery of the 8q24 gene desert.

SUMMARY Protein kinase C (PKC) isozymes are commonly recognized as oncoproteins based on their activation by tumor-promoting phorbol esters. However, accumulating evidence indicates that PKCs can be inhibitory in some cancers, with recent findings propelling a shift in focus to understanding tumor suppressive functions of these enzymes. Here, we report that PKCα acts as a tumor suppressor in PI3K/AKT-driven endometrial cancer. Transcriptional suppression of PKCα is observed in human endometrial tumors in association with aggressive disease and poor prognosis. In murine models, loss of PKCα is rate limiting for endometrial tumor initiation. PKCα tumor suppression involves PP2A-family-dependent inactivation of AKT, which can occur even in the context of genetic hyperactivation of PI3K/AKT signaling by coincident mutations in PTEN, PIK3CA, and/or PIK3R1. Together, our data point to PKCα as a crucial tumor suppressor in the endometrium, with deregulation of a PKCα→PP2A/PP2A-like phosphatase signaling axis contributing to robust AKT activation and enhanced endometrial tumorigenesis.

Background: RAD51 and RecA homologs form a nucleoprotein filament (NPF) that includes an ATP cap, which sandwiches the adenosine nucleotide. Results: The HsRAD51(D316K) ATP cap substitution dramatically enhances recombinase and NPF stability. Conclusion: The HsRAD51(Asp-316) residue forms a salt bridge with ATP that allows more rapid protein turnover. Significance: HsRAD51(D316K) provides a useful reagent for the study of recombinase function in physiological conditions.

The assembly of bacterial RecA, and its human homolog hRAD51, into an operational ADP/ATP-regulated DNA-protein (nucleoprotein) filament is essential for homologous recombination repair (HRR). Yet hRAD51 lacks the coordinated ADP/ATP processing exhibited by RecA and is less efficient in HRR reactions in vitro. In this study, we demonstrate that hXRCC2, one of five other poorly understood non-redundant human mitotic RecA homologs (hRAD51B, hRAD51C, hRAD51D, hXRCC2, and hXRCC3), stimulates hRAD51 ATP processing. hXRCC2 also increases hRAD51-mediated DNA unwinding and strand exchange activities that are integral for HRR. Although there does not seem to be a long-lived interaction between hXRCC2 and hRAD51, we detail a strong adenosine nucleotide-regulated interaction between the hXRCC2-hRAD51D heterodimer and hRAD51. These observations begin to elucidate the separate and specialized functions of the human mitotic RecA homologs that enable an efficient nucleoprotein filament required for HRR.