In PNAS this week, investigators in Germany and the UK show that translation of the proto-oncogene c-Myc is repressed by miR-24c following etoposide-induced DNA damage. "While miR-34c is induced by p53 following DNA damage, we show that in cells lacking p53 this is achieved by an alternative pathway which involves p38 MAPK signaling to MK2," they write, adding that their data reveal c-Myc as a major target of miR-34c. The inhibition of miR-34c activity, the authors report, prevents the arrest in S-phase in response to DNA damage, leading to increased DNA synthesis, damage, and checkpoint activation. They write that their data suggest that "miR-34c serves to remove c-Myc to prevent inappropriate replication which may otherwise lead to genomic instability."
Also in this week's PNAS, researchers at the Hungarian Academy of Sciences report that dual coding in alternative reading frames correlates with intrinsic protein disorder. The team "identified 67 human genes with alternative splice variants comprising a dual-coding region at least 75 nucleotides," and inspected their amino acid composition using the IUPred and PONDR VSL2 algorithms. They calculated the average level of disorder in human proteins in cases of frameshifts; their data suggest that "structural disorder enables these protein products to exist and function without the need of a highly evolved 3D fold," and that "dual coding may be a mechanism for the evolutionary appearance of novel intrinsically disordered regions" with unique functions.
In the PNAS Early Edition, a collaborative research effort presents evidence for the role of miR-155 in modulation of mismatch repair and genomic stability. They show that miR-55 overexpression down-regulates core mismatch repair proteins — hMSH2, hMSH6, and hMLH1 — inducing microsatellite instability and a mutator phenotype. They also report an inverse correlation between miR-155 expression and the expression of the MLHI or MSH2 proteins in human colorectal cancer, adding that "a number of MSI [microsatellite instability] tumors with unknown cause of MMR [mismatch repair] inactivation displayed miR-155 overexpression," supporting the role of miR-155 modulation of MMR as a mechanism of cancer pathogenesis.
Also published online in advance of print, researchers in Germany present evidence that Af9/Mllt3 — associated with leukemia — interferes with Tbr1 expression through the epigenetic modification of the histone H3K79 during the development of the cerebral cortex. They show that "increased expression of TBR1 in Af9 mutants is associated with increased levels of TBR1-regulated expression of NMDAR subunit Nr1." Their study identifies AF9 as a developmentally active epigenetic modifier.