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The only known enzymatic function of the BRCA1 tumor suppressor is the ubiquitin E3 ligase activity mediated by its N-terminal RING domain. Although the enzymatic substrates of BRCA1 are not fully defined, it does catalyze its own ubiquitination to generate polyubiquitinated BRCA1 isoforms that are not targeted for proteasomal degradation. Wu-Baer et al. (p. 2787-2798) show that the UBXN1 protein binds the RING domain of BRCA1 and inhibits its E3 ligase activity. Interestingly, the UBXN1 protein uses a ubiquitin-associated domain to interact preferentially with autoubiquitinated forms of BRCA1, providing a potential mechanism for spatial and/or temporal control of BRCA1 enzymatic function.
Ferguson et al. (p. 2651-2667) show that the Caenorhabditis elegans aip-1 gene is part of a general response to proteosome dysfunction produced by multiple causes. aip-1 is part of a conserved group of proteins including the vertebrate AIRAP protein which are induced by cell stress and interact with the proteosome to augment the clearance of ubiquitinated proteins. This induction of aip-1 requires the actions of both skn-1, which responds to oxidative stress, and hsf-1, which senses unfolded proteins. The combined regulation of this gene could provide specificity to the stressor or delay gene activation until sufficient damage accumulates.
DDB2, a component of ubiquitin ligase (E3) complex, plays a key role in the early stages of global genome nucleotide excision repair (GG-NER). Takedachi et al. (p. 2708-2723) report on DDB2 complex-mediated ubiquitylation around damaged sites in chromatin. At the damaged sites, E3 activity is enhanced by dissociation of CSN and by interaction with XPC. In contrast, Ku70/86, which is found to interact with the DDB2 complex in a UV-dependent manner, particularly inhibits the autoubiquitylation of DDB2. Furthermore, DDB2 complex-mediated ubiquitylation contributes to the recruitment of XPA. These findings provide critical insights into the early stages of GG-NER.
Premature senescence in response to reactive oxygen species (ROS) is an important mechanism that prevents accumulation of mutant cells. Roy et al. (p. 2681-2692) revealed that DDB2, a DNA repair protein, plays a significant role in that process. ROS stimulate expression of DDB2, which in turn represses transcription of antioxidant genes, causing further accumulation of ROS. That feedback regulation of ROS accumulation by DDB2 is critical for premature senescence induced by oncogenic Ras, DNA damage, and other oxidative stressors. The observations provide new insights into the mechanisms that sense the mutagenic level of ROS to induce premature senescence.
It has recently become appreciated that covalent modifications in the histone globular domains carry essential information for development and gene regulation. Using novel multiplex chromosome immunoprecipitation-single-nucleotide primer extension assays, Singh et al. (p. 2693-2707) mapped the allele-specific enrichment of H3K79 methylation and H4K91 acetylation at the differentially methylated regions (DMRs) of 11 imprinted domains. At maternally and paternally methylated DMRs, H3K79me3 was biased toward the CpG-methylated allele whereas H4K91ac, H3K79me1, and H3K79me2 were biased toward the unmethylated allele. Interestingly, one methyl group difference specified H3K79me2's association with euchromatin and H3K79me3's association with heterochromatin, at the functionally opposite and epigenetically distinct imprinted alleles.
GATA and RUNX transcription factors play key roles during hematopoiesis in humans and drosophila. Using a genome-wide RNA interference screen strategy, Gobert et al. (p. 2837-2848) identified a large set of conserved factors controlling the activity of the Drosophila GATA/RUNX complex Srp/Lz. Interestingly, among the four subunits of the Mediator complex CDK8 regulatory module, the Med12/Med13 pair participates as the coactivator of Srp/Lz during Lz+ blood cell differentiation independently of the CycC/Cdk8 pair, yet the four CDK8 module subunits control Lz+ blood cell number. These data underline the flexibility of the CDK8 module, whose subunits are reiteratively and specifically used at different stages of development.