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Mol Cell Biol. 2010 January; 30(1): 20–21.
PMCID: PMC2798292

Articles of Significant Interest Selected from This Issue by the Editors

Regulating Merlin Conformation: an Open and Shut Case?

Activation of the tumor suppressor merlin is thought to be achieved by transition from an open conformation to a closed conformation. As with other ERM proteins, this closed conformation is assumed to be mediated by the intramolecular binding of the N-terminal FERM domain to the C-terminal domain (CTD). The fluorescence resonance energy transfer (FRET) study by Hennigan et al. (p. 54-67) challenges this notion. Exhaustively characterized FRET probes reveal no evidence for an open, extended conformation. The closed conformation persists even when the FERM domain and CTD are absent, indicating a role for the central α-helical domain in a more subtle and complex model of merlin regulation.

A Confirmed In Vivo Role for αNAC in Bone

The physiological role of the multifunctional protein nascent polypeptide-associated complex and coactivator alpha (αNAC) remains to be established. Conventional gene targeting of αNAC is embryonic lethal. To circumvent this difficulty, Meury et al. (p. 43-53) engineered a knock-in mutation that inactivates a phosphoacceptor site responsible for nuclear translocation of αNAC. The mutation resulted in decreased nuclear αNAC, with reduced osteocalcin and α1(I) collagen transcription. Mutant bones had a reduced amount of immature, woven matrix. This study identifies a novel αNAC transcriptional target, α1(I) collagen, and represents the first demonstration of αNAC's importance in osteoblastic gene expression and bone formation in vivo.

Extending Hypoxia-Inducible Factor Activity through Histone Demethylation

Tumor cells typically outgrow their blood supply, depleting their surroundings of nutrients and oxygen. In response to cellular hypoxia, the hypoxia-inducible transcription factors (HIFs) directly regulate expression of genes promoting adaptation to hypoxia. HIF also induces several histone demethylases, implying that it may indirectly enhance gene expression at the epigenetic level. Krieg et al. (p. 344-353) demonstrate that hypoxic induction of the histone demethylase JMJD1A demethylates histone H3K9 near the promoters of target genes, maximizing hypoxic expression and establishing a mechanism for HIF to promote tumorigenesis through epigenetic modification.

Phosphorylation Regulates Structure and Functions of an Intrinsically Disordered Activation Domain

Intrinsically disordered (ID) regions are disproportionately higher in cell signaling proteins and are predicted to have much higher frequency of phosphorylation sites than ordered regions, suggesting important roles in their regulatory capacity. Garza et al. (p. 220-230) observed phosphorylation-induced secondary/tertiary structure formation in an otherwise ID activation domain of a transcription factor, which facilitates its interactions with specific coregulatory proteins and subsequent transcriptional activity, providing a potential mechanism through which ID domains function under physiological conditions. In cell signaling, several kinases produce diverse cellular responses; these results should provide a mechanism by which transcription factors’ ID activation domains may regulate expression of a target gene(s).

The Replication Stress Response and the Ubiquitin System: a New Link in Maintaining Genomic Integrity

Accurate DNA replication is critical to the faithful transmission of genomic information from one generation to the next. Under conditions of replication stress, a checkpoint response is activated to stabilize replication forks and prevent cell cycle progression, but the precise mechanism of how this is achieved is not clear. Kile and Koepp (p. 160-171) now show that the replication stress response inhibits the proteolysis of the F-box protein Dia2, an E3 ligase component required for maintaining genomic integrity. This work suggests that one outcome of the replication stress response is to promote Dia2-dependent ubiquitin ligase activity.

RKTG Brakes Gβγ Signaling at the Golgi Apparatus

As a component of heterotrimeric G proteins, Gβγ is involved in the regulation of many signaling events such as desensitization of GPCR by recruitment of GRK. Previous work focused mainly on modulation of Gβγ activities at the plasma membrane. Jiang et al. (p. 78-90) demonstrate that RKTG, a Golgi apparatus-localized protein, can regulate Gβ-mediated signaling in a spatio-temporal manner. Upon GPCR activation, the released Gβγ subunit is dynamically tethered to the Golgi apparatus via interaction with RKTG, putting a hold to the downstream signaling of Gβγ. Consequently, desensitization of GPCR is compromised with overexpression of RKTG and Gbg-mediated AKT phosphorylation is enhanced with downregulation of RKTG.

A New Activity for TFIIF: Eviction of Noncoding RNAs from RNA Polymerase II

Two noncoding RNAs (ncRNAs) that are upregulated in mouse cells during heat shock, B1 RNA and B2 RNA, bind tightly and competitively to RNA polymerase II (Pol II). Once bound, B2 RNA represses transcription, whereas B1 RNA does not. Wagner et al. (p. 91-97) find that TFIIF, a general factor for Pol II transcription, facilitates the dissociation of B1 RNA from Pol II, allowing B2 RNA to bind Pol II and repress transcription. This activity could also allow TFIIF to evict RNAs that spuriously bind Pol II in cells, thereby providing access to ncRNAs that function to control transcription.

Articles from Molecular and Cellular Biology are provided here courtesy of American Society for Microbiology (ASM)