No abstract

ATP-dependent chromatin-remodeling complexes (remodelers) are essential regulators of chromatin structure and gene transcription. How remodelers can act in a gene-selective manner has remained enigmatic. A yeast two-hybrid screen for proteins binding the Drosophila transcription factor Tramtrack69 (TTK69) identified MEP1. Proteomic characterization revealed that MEP1 is a tightly associated subunit of the NuRD remodeler, harboring the Mi2 enzymatic core ATPase. In addition, we identified the fly homolog of human Deleted in oral cancer 1 (DOC1), also known as CDK2-associated protein 1 (CDK2AP1), as a bona fide NuRD subunit. Biochemical and genetic assays supported the functional association between MEP1, Mi2, and TTK69. Genomewide expression analysis established that TTK69, MEP1, and Mi2 cooperate closely to control transcription. The TTK69 transcriptome profile correlates poorly with remodelers other than NuRD, emphasizing the selectivity of remodeler action. On the genes examined, TTK69 is able to bind chromatin in the absence of NuRD, but targeting of NuRD is dependent on TTK69. Thus, there appears to be a hierarchical relationship in which transcription factor binding precedes remodeler recruitment.Chromatin is the natural template of the eukaryotic transcription machinery. Consequently, regulation of gene expression involves the interplay between sequence-specific transcription factors, the basal machinery, coregulators, and enzymes that modulate chromatin structure. ATP-dependent chromatin-remodeling factors (remodelers) constitute one class of enzymes that target chromatin. The basic biochemical activity of remodelers is to use the energy of ATP hydrolysis to move or eject nucleosomes (8). Although their in vitro activity might suggest that remodelers act in a generic way, it has become clear that different remodelers perform distinct, nonredundant functions. An early example of functional specialization was our finding that the Brahma (BRM) remodeling complexes, but not ISWI remodelers, act as chromatin-specific coactivators for the transcription factor ZESTE (15). Conversely, unlike ISWI, the BRM remodelers were unable to order a nucleosomal array. Moreover, several studies have demonstrated that different remodelers control distinct biological processes (4, 8, 24).Currently, four major classes of remodelers are recognized, based on their ATPase and accessory subunits (8). These comprise the SWI/SNF, ISWI, CHD, and INO80 families. Mi2 (also known as CHD4) is the founding member of the CHD family of remodelers, characterized by the presence of a tandem chromodomain in the ATPase subunit (9). A unique aspect of NuRD is its coupling of remodeling and histone deacetylase (HDAC) activities in one complex. Although there is some variability between the various vertebrate NuRD complexes described so far, the key subunits of NuRD are the Mi2 ATPase, the protein deacetylases HDAC1 and HDAC2, metastasis-associated proteins MTA1, MTA2, and MTA3, the retinoblastoma-associated histone binding proteins RBP46 and RBP48...

Highlights d RQC factors involved in disassembling collided ribosomes suppress the cGAS pathway d Ribosomes interact with cGAS, stimulating its DNAdependent activity d cGAS preferentially interacts with collided ribosomes d Ribosome collision leads to re-localization of cGAS to the cytosol and ISG activation

Resistance to targeted therapies is a major problem in cancer treatment. The epidermal growth factor receptor (EGFR) antibody drugs are effective in a subset of colorectal cancers, but the molecular mechanisms of resistance are understood poorly. Genes involved in epigenetic regulation are frequently deregulated in cancer, raising the possibility that such genes also contribute to drug resistance. Using a focused RNA interference library for genes involved in epigenetic regulation, we identify sirtuin2 (SIRT2), an NAD(+)-dependent deacetylase, as a modulator of the response to EGFR inhibitors in colon and lung cancer. SIRT2 loss also conferred resistance to BRAF and MEK inhibitors in BRAF mutant melanoma and KRAS mutant colon cancers, respectively. These results warrant further investigation into the potential role of SIRT2 in resistance to drugs that act in the receptor tyrosine kinase-RAS-RAF-MEK-ERK signaling pathway.