Artículos Científicos

Polμ deficiency increases resistance to oxidative damage and delays liver aging

PLoS One. 2014; 9(4): e93074.

Escudero B, Lucas D, Albo C, Dhup S, Bacher 4, Sánchez-Muñoz A, Fernández M, Rivera-Torres J, Carmona RM, Fuster E, Carreiro C, Bernad R, González M, Andrés V, Blanco L, Roche E, Fabregat I, Samper E, Bernad A.

PLoS One. 2014; 9(4): e93074Polμ is an error-prone PolX polymerase that contributes to classical NHEJ DNA repair. Mice lacking Polμ (Polμ−/−) show altered hematopoiesis homeostasis and DSB repair and a more pronounced nucleolytic resection of some V(D)J junctions.

We previously showed that Polμ−/− mice have increased learning capacity at old ages, suggesting delayed brain aging. Here we investigated the effect of Polμ−/− deficiency on liver aging. We found that old Polμ−/− mice (>20 month) have greater liver regenerative capacity compared with wt animals. Old Polμ−/− liver showed reduced genomic instability and increased apoptosis resistance. However, Polμ−/− mice did not show an extended life span and other organs (e.g., heart) aged normally.

Our results suggest that Polμ deficiency activates transcriptional networks that reduce constitutive apoptosis, leading to enhanced liver repair at old age.

The hypervariable amino-terminus of p1 protease modulates potyviral replication and host defense responses

PLoS Pathog. 2014; 10(3): e1003985.

Pasin F, Simón-Mateo C, García JA.

PLoS Pathog. 2014; 10(3): e1003985The replication of many RNA viruses involves the translation of polyproteins, whose processing by endopeptidases is a critical step for the release of functional subunits. P1 is the first protease encoded in plant potyvirus genomes; once activated by an as-yet-unknown host factor, it acts in cis on its own C-terminal end, hydrolyzing the P1-HCPro junction. Earlier research suggests that P1 cooperates with HCPro to inhibit host RNA silencing defenses.

Using Plum pox virus as a model, we show that although P1 does not have a major direct role in RNA silencing suppression, it can indeed modulate HCPro function by its self-cleavage activity. To study P1 protease regulation, we used bioinformatic analysis and in vitro activity experiments to map the core C-terminal catalytic domain. We present evidence that the hypervariable region that precedes the protease domain is predicted as intrinsically disordered, and that it behaves as a negative regulator of P1 proteolytic activity in in vitro cleavage assays. In viral infections, removal of the P1 protease antagonistic regulator is associated with greater symptom severity, induction of salicylate-dependent pathogenesis-related proteins, and reduced viral loads.

We suggest that fine modulation of a viral protease activity has evolved to keep viral amplification below host-detrimental levels, and thus to maintain higher long-term replicative capacity.

Dido3-dependent HDAC6 targeting controls cilium size

Nat Commun. 2014; doi: 10.1038/ncomms4500.

Sánchez de Diego A, Guerrero AA, Martínez-A C, van Wely KHM.

Nat Commun. 2014; doi: 10.1038/ncomms450Primary cilia are involved in a variety of physiological processes such as sensing of the environment, cell growth and development. Numerous developmental disorders and pathologies arise from defects in these organelles. Multiple proteins that promote formation and disassembly of the primary cilium have been identified, but little is known about the mechanisms that control steady-state cilium size.

Here, we show that death inducer obliterator (Dido3)-dependent targeting of histone deacetylase 6 (HDAC6) is a key determinant of cilium size in growth-arrested cells. The amount of either protein negatively correlates with cilium size. Dido3 availability at the centrosome governs ciliary HDAC6 levels, and redistribution of the two proteins controls tubulin acetylation. In turn, basal body localization of Dido3 and HDAC6 depends on the actin network, previously shown to limit cilium size independent of the cell cycle. These results show that not only kinase-dependent activation of a deacetylase but also its subcellular distribution controls substrate selection.

Genetic architecture of naturally occurring quantitative traits in plants: an updated synthesis

Curr Opin Plant Biol. 2014; 18C: 37-43.

Alonso-Blanco C, Méndez-Vigo B.

Curr Opin Plant Biol. 2014; 18C: 37-43Deciphering the genetic and molecular bases of quantitative variation is a long-standing challenge in plant biology because it is essential for understanding evolution and for accelerating plant breeding. Recent multi-trait analyses at different phenotypic levels are uncovering the pleiotropy and the genetic regulation underlying high-level complex traits. Thus, the number of known causal loci, genes and nucleotide polymorphisms is expanding.

Current plant causal catalogs contain ∼400 genes and natural polymorphisms revealing several dysfunctional allelic series that involve multiple mutations. In addition, repeated evolution of quantitative traits mediated by large effect alleles is found across plant phylogeny. Finally, systematic analyses of genetic and environmental interactions are beginning to elucidate the molecular mechanisms of relevant interactions.

Targeted degradation of abscisic acid receptors is mediated by the ubiquitin ligase substrate adaptor DDA1 in Arabidopsis

Plant Cell. 2014 Feb 21.

Irigoyen ML1, Iniesto E, Rodriguez L, Puga MI, Yanagawa Y, Pick E, Strickland E, Paz-Ares J, Wei N, De Jaeger G, Rodriguez PL, Deng XW, Rubio V.

Plant Cell. 2014 Feb 21CULLIN4-RING E3 ubiquitin ligases (CRL4s) regulate key developmental and stress responses in eukaryotes. Studies in both animals and plants have led to the identification of many CRL4 targets as well as specific regulatory mechanisms that modulate their function. The latter involve COP10-DET1-DDB1 (CDD)–related complexes, which have been proposed to facilitate target recognition by CRL4, although the molecular basis for this activity remains largely unknown.

Here, we provide evidence that Arabidopsis thaliana DET1-, DDB1-ASSOCIATED1 (DDA1), as part of the CDD complex, provides substrate specificity for CRL4 by interacting with ubiquitination targets. Thus, we show that DDA1 binds to the abscisic acid (ABA) receptor PYL8, as well as PYL4 and PYL9, in vivo and facilitates its proteasomal degradation. Accordingly, we found that DDA1 negatively regulates ABA-mediated developmental responses, including inhibition of seed germination, seedling establishment, and root growth. All other CDD components displayed a similar regulatory function, although they did not directly interact with PYL8. Interestingly, DDA1-mediated destabilization of PYL8 is counteracted by ABA, which protects PYL8 by limiting its polyubiquitination.

Altogether, our data establish a function for DDA1 as a substrate receptor for CRL4-CDD complexes and uncover a mechanism for the desensitization of ABA signaling based on the regulation of ABA receptor stability.