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Proteasomes on the Chromosome Cell Research (2017) 27:602-603 602 Cell Research (2017) 27:602-603. © 2017 IBCB, SIBS, CAS All rights reserved 1001-0602/17 $ 32.00 RESEARCH HIGHLIGHT www.nature.com/cr Proteasomes on the chromosome Cell Research (2017) 27:602-603. doi:10.1038/cr.2017.28; published online 7 March 2017 Targeted proteolysis plays an this process, both in mediating homolog ligases, respectively, as RN components important role in the execution and association and in providing crossovers that impact crossover formation [5, 6]. regulation of many cellular events. that tether homologs and ensure their In the first of the two papers, Ahuja et Two recent papers in Science identify accurate segregation. Meiotic recom- al. [7] report that budding yeast pre9∆ novel roles for proteasome-mediated bination is initiated by DNA double- mutants, which lack a nonessential proteolysis in homologous chromo- strand breaks (DSBs) at many sites proteasome subunit, display defects in some pairing, recombination, and along chromosomes, and the multiple meiotic DSB repair, in chromosome segregation during meiosis. interhomolog interactions formed by pairing and synapsis, and in crossover Protein degradation by the 26S pro- DSB repair drive homolog association, formation. Similar defects are seen, teasome drives a variety of processes culminating in the end-to-end homolog but to a lesser extent, in cells treated central to the cell cycle, growth, and dif- synapsis by a protein structure called with the proteasome inhibitor MG132. ferentiation. Proteins are targeted to the the synaptonemal complex (SC) [3]. These defects all can be ascribed to proteasome by covalently ligated chains SC-associated focal protein complexes, a failure to remove nonhomologous of ubiquitin, a small (8.5 kDa) protein. here called recombination nodules synapsis. In budding yeast, centromeres The protein ligases that catalyze ubiqui- (RNs), form around and stabilize inter- are clustered early in meiosis, and SC tin addition recognize targets by direct homolog recombination intermediates recruited to these clustered centromeres interaction or by binding to sites of and thus facilitate homolog pairing. pairs them without regard to homology post-translational modification (PTM). Later, most RNs are removed, and [8]. Thus, most initial SC formation One such PTM is SUMOylation. SUMO associated recombination intermedi- occurs between nonhomologous chro- (small ubiquitin-like moiety) ligation ates are disassembled as noncrossover mosomes. Ahuja et al. show that, in can disrupt protein-protein interactions recombinants. A smaller number of pre9∆ mutants, this early SC is never or, conversely, drive protein complex RNs are preserved and the recombina- taken apart, and homologs never prop- assembly via interactions between tion intermediates that they contain are erly associate or synapse. This results in SUMOylated proteins and proteins that resolved as crossovers. While normally decreased interhomolog recombination, contain SUMO interaction modules promoting interhomolog pairing and unrepaired DSBs, and a general reduc- (SIMs) [1]. One such type of interac- crossover formation, SC can also form tion in crossovers. Thus, it appears that tion involves the recognition of SU- between stably paired nohomologous full proteasome function is needed to MOylated proteins by SUMO targeted chromosomes that are fortuitously jux- remodel or remove SC proteins from ubiquitin ligases (STUBLs), which cata- taposed. Unless this nonhomologous sites of nonhomologous pairing (Figure lyze polyubiquitylation and thus effect synapsis is removed, it can interfere 1A). Patterns of proteasome recruitment proteasome-mediated degradation [2]. with homologous chromosome pairing, to meiotic chromosomes in early meio- While PTM-dependent proteasome- recombination, and ultimately proper sis are consistent with this suggestion; mediated degradation has been exten- chromosome segregation. other proteasome localization data sug- sively documented for the mitotic cell What roles do SUMO, ubiquitin, and gest a role in the disassembly of the SC cycle, considerably less is known about the 26S proteasome play in the chromo- at the end of meiosis I prophase. roles of this process during meiosis. some pairing and segregation events of In the second of the two papers, Rao Meiosis involves the division of the meiosis? Two recent papers, published et al. [9] examine roles for SUMO, diploid genome into haploid gametes, in Science, address this question. Previ- ubiquitin, and the proteasome in RN dy- and thus requires separation of homolo- ous work, primarily in budding yeast, namics and crossover designation dur- gous chromosomes of different parental has implicated SUMO as playing impor- ing mouse spermatogenesis. They used origin (hereafter called homologs) at the tant roles in SC assembly [4], and stud- immunocytology to examine meiotic first of two nuclear divisions (meiosis I). ies in mice have identified RNF212 and chromosome spreads in mutants lacking Homologous recombination is critical to HEI10, putative SUMO and ubiquitin RNF212 or HEI10, and upon chemical SPRINGER NATURE | Cell Research | Vol 27 No 5 | May 2017 603 Taken together, these two papers document, for the first time, a role for SUMO- and ubiquitin-mediated pro- teasome targeting in normal meiotic chromosome transactions and recombi- nation. In particular, by showing that the proteasome is recruited to its “sites of action” on meiotic chromosomes, they suggest that the proteasome is an active participant in the orderly disassembly of chromosome structures, rather than simply degrading proteins removed by other processes. The two papers open the door for further investigation, including identification of the relevant targets of SUMOylation, ubiquitylation Figure 1 (A) The budding yeast 26S proteasome (red) disassembles synaptonemal and proteolytic degradation, as well as complex at sites of nonhomologous synapsis between centromeres, freeing up ho- the regulatory mechanisms by which mologs to pair and synapse. The proteasome may also remove synaptonemal com- plex from other sites of nonhomologous synapsis. (B) Recombination nodule (RN) these events are controlled. dynamics in male mouse meiosis. RNF212 (blue)-catalyzed SUMOylation stabilizes RNs and recombination intermediates, promoting homolog pairing, but also recruits Michael Lichten1 HEI10 (purple). HEI10 ubiquitylates yet-to-be determined targets in RNs to recruit the 26S proteasome, destabilizing most RNs; at a subset of RNs, RNF212 activity 1Laboratory of Biochemistry and Molecular dominates. These RNs perdure and the recombination intermediates that they con- Biology, Center for Cancer Research, National tain are resolved as crossovers. Cancer Institute, Bethesda, MA 20892-4260, USA Correspondence: Michael Lichten E-mail: [email protected] inhibition of SUMOylation, ubiquitin STUBL, which ubiquitylates RN pro- References activation, or proteasome-mediated pro- teins and targets them for degradation teolysis. They find that SUMOylation, by the proteasome, thus destabilizing 1 Jentsch S, Psakhye I. Annu Rev Genet 2013; ubiquitylation, and proteasome activity RNs and causing the disassembly of 47:167-186. 2 Nie M, Boddy MN. Biomolecules 2016; are all required for efficient homolog underlying recombination intermedi- 6:14. synapsis, normal homologous recombi- ates as noncrossovers. At a few RNs, 3 Cahoon CK, Hawley RS. Nat Struct Mol nation, and normal RN dynamics. Based RNF212 activity predominates over Biol 2016; 23:369-377. on this and previous work [6], Rao and HEI10-mediated destabilization. These 4 Watts FZ, Hoffmann E. Bioessays 2011; 33:529-537. coworkers propose a model (Figure RNs and the underlying recombination 5 Reynolds A, Qiao H, Yang Y, et al. Nat Gen- 1B) in which crossover/noncrossover intermediates perdure, and ultimately et 2013; 45:269-278. decision is implemented by an unstable are resolved as crossovers at the end 6 Qiao H, Prasada Rao HB, Yang Y, et al. Nat circular feedback loop (referred to by of meiosis I prophase. The factors that Genet 2014; 46:194-199. 7 Ahuja JS, Sandhu R, Mainpal R, et al. Sci- the authors as a “SUMO-ubiquitin determine whether HEI10 or RNF212 ence 2017; 355:408-411. relay”) with two stable outcomes. Ini- activity will predominate at a given RN 8 Tsubouchi T, Roeder GS. Science 2005; tially, RNF212-catalyzed SUMOylation remain unknown, but they must involve 308:870-873. promotes RN assembly, thus stabilizing signaling over considerable distances, 9 Rao HB, Qiao H, Bhatt SK, et al. Science 2017; 355:403-407. recombination intermediates to promote since most organisms display non- 10 Zickler D, Kleckner N. Semin Cell Dev Biol synapsis. At the same time, RNF212- random spacing between stable RNs 2016; 54:135-148. deposited SUMO recruits the HEI10 and resulting crossovers [10]. www.cell-research.com | Cell Research | SPRINGER NATURE.
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