SUMMARY PARAGRAPH for NHP6A
NHP6A and NHP6B encode highly homologous proteins, each containing a single High Mobility Group (HMG) B domain, that are involved in modulation of chromatin structure (reviewed in 6). Though the short amino termini differ, they are 89 percent identical over the 90 amino acid core HMG B domain. Single null mutants in either nhp6a or nhp6b are viable with no phenotype, but the double knockout exhibits a slow growth phenotype at 30 degrees C and is inviable at 38 degrees C (2). Where both proteins have been assayed individually in vitro, slight differences are sometimes observed (e.g., see 10), but most biochemical experiments have been done only with purified Nhp6a protein. The two proteins are considered functionally equivalent and are collectively referred to as Nhp6.
Numerous genetic interactions, both synthetic lethality/sickness in combination with mutations in known chromatin remodelers (including FACT, Swi/Snf, RSC, Ssn6p, and Spt6p) and suppression of mutations by overexpression of Nhp6, indicate a role for Nhp6 in modulation of chromatin structure (reviewed in 6). These proteins are abundant, with approximately one molecule of Nhp6Ap present for every one to two nucleosomes, and one tenth as much Nhp6Bp (2), consistent with the observed 3-10 fold difference in mRNA levels (1). Nhp6 binds to DNA without sequence specificity, bending it sharply (11). Nhp6Ap binds directly to nucleosomes (12), loosening, or "remodelling", the structure of the core nucleosome (5, 3). The role of Nhp6 in the context of the yeast FACT complex (comprised of Spt16p and Pob3p) is the best characterized of its many interactions with chromatin remodelling activities (reviewed in 6). Unlike mammalian FACT, where one of the subunits contains an HMB domain, yeast FACT does not, instead relying on the external HMG domain of Nhp6 to localize it to chromatin where it contributes to the structural remodelling of the nucleosome begun by the binding of Nhp6 alone. However, the role of Nhp6 is not limited to its involvement with the FACT complex; it may serve to localize a number of different chromatin remodelling activities to the appropropriate places within the chromatin. Nhp6 activity contributes to the formation and correct placement of preinitiation complexes (PICs) for certain genes transcribed by either RNA polymerase II or RNA polymerase III, including the essential U6 snRNA (encoded by snR6 and transcribed by RNAP III), though it is possible that this is an indirect effect of the chromatin remodelling activities of Nhp6 (reviewed in 6). Nhp6 is also implicated in DNA repair, both as part of the FACT complex (13) and independently of FACT as well. In vitro, Nhp6Ap and the MutS-alpha complex, composed of Msh2p and Msh6p, colocalize with DNA containing mismatches (14).
In mammals the High Mobility Group B proteins encoded by HMGB1 and HMGB2 (originally called HMG1 and HMG2) are abundant and play important roles in the assembly of nucleoprotein complexes in processes including transcription, DNA repair, and V(D)J recombination. NHP6A and NHP6B appear to be the functional equivalents of HMGB1 and HMGB2. However, the mammalian proteins contain two repeats of the HMG domain and an acidic C-terminal tail, while the yeast proteins contain only a single HMG domain and no tail (reviewed in 7).
Last updated: 2010-03-30