It takes teamwork to modify chromatin

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Science  12 Feb 2016:
Vol. 351, Issue 6274, pp. 667
DOI: 10.1126/science.aaf1495

To participate in the choreography of signals that occur on the chromosome during gene activation, many multisubunit chromatin-modifying complexes contain more than one enzyme that chemically alter histones, the protein constituent of chromatin. These complexes themselves often contain modules or clusters of subunits dedicated to specific functions of the complex (1). The Spt-Ada-Gcn5 acetyltransferase (SAGA) complex is a good example of this organization. It is highly conserved from yeast to humans, contains up to 20 subunits, and is about 2 MDa in size. SAGA contains several functional modules, two of which have enzymatic activities and others that mediate SAGA interactions with proteins that control transcription (2). Hence, teamwork between these modules is crucial for the steps leading to transcription initiation and its transition to RNA elongation (3). Even within each module, teamwork between individual subunits is necessary to promote accurate enzymatic activity. On page 725 in this issue, Morgan et al. (4) provide structural and biochemical data that nicely illustrate cooperation between subunits within the module that contains a histone deubiquitinase, and between this module and the remainder of the SAGA complex.

Ubiquitination of histone H2B provides an important checkpoint in the transition from the early initiated form of RNA polymerase II to the full elongating form. This change is governed by the phosphorylation status of heptapeptide repeats in the carboxyl-terminal domain (CTD) of the largest subunit of RNA polymerase II. Immediately after initiation, these repeats are phosphorylated on serine 5 and serine 7, which brings cofactors to the polymerase that facilitate early elongation steps. These repeats are then phosphorylated on serine 2, which recruits cofactors that function during subsequent transcription elongation (5). Monoubiquitination of the carboxyl-terminal tail of H2B blocks the enzyme that phosphorylates serine 2 of the CTD repeats, thus regulating the transition to full elongation. Deubiquitination of H2B by the SAGA complex allows phosphorylation of serine 2 of the CTD repeats, promoting transition from the early elongation to the full elongation form of RNA polymerase II (6).

DUB module.

Different subunits of the DUB module of the SAGA complex play distinct roles in regulating its ubiquitin protease activity. Sgf73 attaches the DUB module to the SAGA complex;Sgf11 provides specificity for H2B by recognizing the acidic patch on the nucleosomal H2A/H2B dimer. This and additional contacts between the DUB module and the nucleosome position Ubp8 at the carboxyl-terminal tail of H2B. Ubp8 is the ubiquitin protease that clips ubiquitin off the carboxyl-terminal tail of H2B.


In addition to containing a histone acetyltransferase module that acts on histones H2B and H3, SAGA contains a deubiquitinase (DUB) module comprising the ubiquitin protease Ubp8, and the subunits Sgf11, Sgf73, and Sus1. These subunits have unique roles in H2B deubiquitination (7). Whereas Ubp8 removes ubiquitin from H2B, Sgf11 largely determines its specificity for H2B. By analyzing the crystal structure (at 3.8 Å resolution) of the DUB module bound to a ubiquitinated nucleosome modified on histone H2B, Morgan et al. show that Sgf11 uses a zinc finger domain to bind to the acidic patch on the H2A/H2B dimer. This interaction, along with additional contacts, positions Ubp8 in proximity to the ubiquitin on H2B. Interestingly, the acidic patch also binds to the H4 tail from an adjacent nucleosome (8), suggesting that this acidic patch plays a role in higher-order nucleosome packing. In addition, several other nucleosome-binding proteins and complexes recognize the acidic patch (9), suggesting that binding of these proteins or Sgf11 could also affect nucleosome packing. Sgf73 attaches the DUB module to the remainder of the SAGA complex. Morgan et al. also observed that the amino terminus of Sgf73 is buried within the DUB module, whereas the carboxyl terminus attaches to the SAGA complex (4, 10, 11). Attachment of the DUB module to SAGA is important for regulating its deubiquitination activity. In the absence of Sgf73, the DUB module detaches from SAGA and becomes inactive in yeast but hyperactive in flies (10, 12).

The structural data provided by Morgan et al. provide new insights into how cooperation among the DUB module subunits enables the SAGA complex to control transcription (see the figure). It also offers a possible mechanism for how H2A phosphorylation affects deubiquitination.

References and Notes

Acknowledgments: I thank S. M. Abmayr for help. This work was supported by National Institute of General Medical Sciences grant GM099945 and the Stowers Institute.

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