Heterodimer binding to DNA

Ijpcnbcrg, A., jeannin, E., Wahli, W., and Desvetgne, B. (1997). Polarity acid specific sequence requirements of peroxisome proliferator activated receptor (PPAR)/retinoid X receptor heterodimer binding to DNA. /. Bibf. Chem. 272,2010S-20117. 

In nonhomologous end joining of DNA, the Ku70Ku80 protein heterodimer binds to DNA at the site of a DSB, aligning the halves of the DSB. The strand ends are accessible to nucleases, DNA polymerases, and DNA ligases that collectively repair the DSB. 

Figure 9.12 Schematic diagram of the structure of the heterodimeric yeast transcription factor Mat a2-Mat al bound to DNA. Both Mat o2 and Mat al are homeodomains containing the helix-turn-helix motif. The first helix in this motif is colored blue and the second, the recognition helix, is red. (a) The assumed structure of the Mat al homeodomain in the absence of DNA, based on Its sequence similarity to other homeodomains of known structure, (b) The structure of the Mat o2 homeodomain. The C-terminal tail (dotted) is flexible in the monomer and has no defined structure, (c) The structure of the Mat a 1-Mat a2-DNA complex. The C-terminal domain of Mat a2 (yellow) folds into an a helix (4) in the complex and interacts with the first two helices of Mat a2, to form a heterodimer that binds to DNA. (Adapted from B.J. Andrews and M.S. Donoviel, Science 270 251-253, 1995.)...

The technique has been used for the total synthesis of truncated forms of the basic/helix-loop-helix/zipper domains of the nuclear protein transcription regulation factors cMyc and Max. These were covalently joined through an oxime bond to form a single protein-like entity with two amino termini, i.e. cMyc-Max heterodimer and Max-Max homodimer, each 172 residues, which bind to DNA and activate or inhibit mRNA transcription. 103 ... 

Most transcription activators bind to DNA as a dimer or higher multimer (see 2.4). The dimerization relies on structural motifs which commonly occur in many different proteins. Examples for dimerization motifs are the helix-loop-hdix motif and the leucine zipper. The dimerization motifs permit the formation of DNA-boimd homodimers or heterodimers, depending upon whether the same or different proteins interact with each other (Fig. 1.38). The different dimers have different requirements for the... 

Each of the monomeric proteins c-jun and c-fos, as well as other members of the leucine zipper family, has an N-terminal DNA-binding domain rich in positively charged basic amino acid side chains, an activation domain that can interact with other proteins in the initiation complex, and the leucine-rich dimerization domain.363 The parallel coiled-coil structure (Fig. 2-21) allows for formation of either homodimers or heterodimers. However, cFos alone does not bind to DNA significantly and the cjun/cFos heterodimer binds much more tightly than does cjun alone.364 The yeast transcriptional activator protein GCN4 binds to the same 5 -TGACTCA sequence as does the mammalian AP-1 and also has a leucine zipper structure.360 364 365... 

In yeast model systems it has been observed that myc is a transcription activator but only when present in a heterodimer with max. Max appears to be essential for DNA binding. Max dimer can bind to DNA on its own but it does not activate transcription on its own. Mammalian genes that are normally activated by myc are still not known. 

The oncogene of the FBJ murine osteosarcoma virus (fos) codes for a related nuclear protein that participates in transcriptional regulation. In human fibroblasts the fos protein is mostly associated with c-jun. The fos-jun complex binds specifically to DNA. Since fos alone does not show specific DNA binding, it is believed that jun is responsible for this affinity. Although jun can form homodimers that bind to DNA, the heterodimers formed between fos and jun show a greater affinity. The heterodimers are also more effective in transcription activation therefore the heterodimer is probably the functionally relevant state of the jun and fos proteins. 

In the presence of all- trans- or 9-ds-retinoic acid, the receptor heterodimers are transcriptional activators. However, the heterodimers will also bind to DNA in the absence of retinoic acid, in which case they act as repressors of gene expression (Fujita and Mitsuhashi, 1999). 

The structure of the heterodimeric transcription factor Fos/Jun bound to DNA has been solved. Jun contains a basic leucine zipper (bZIP) motif. Formation of a stable heterodimer is necessary for binding to DNA (see below). 

In NHEJ in eukaryotes, the Ku heterodimer binds to both ends of the double-strand break (32) and recruits DNA-PKcs and the ligase IV-XRCC4 heterodimer. These then ligate both ends of the double-strand break regardless of whether they actually come from the same chromosome (33). In NHEJ, Artemis is the end-processing nuclease (34) (Fig. 8). 

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