The SUMO Isopeptidase SENP6 Functions as a Rheostat of Chromatin Residency in Genome Maintenance and Chromosome Dynamics

Abstract

Highlights d The N-terminal region of SENP6 binds to SUMO chains d SENP6 controls SUMOylation of cohesin and regulates sister chromatid cohesion d SENP6 regulates the ATR-Chk1 DNA damage checkpoint d SENP6 orchestrates chromatin dynamics by balancing chromatin residency of proteins

SUMO Chains Rule on Chromatin Occupancy

“…Noteworthy, in the yeast S. cerevisiae the CENP-A ortholog Cse4 is targeted for degradation by the Slx5/8 StUbL thereby preventing its mislocalization to euchromatin (Ohkuni et al, 2016). In mammalian cells, CENP-B dynamics at centromeres is also likely directly regulated by SUMO-primed RNF4-dependent proteasomal degradation (Maalouf et al, 2018), which is consistent with the identification of CENP-B as a major SENP6 target in proteomic studies (Liebelt et al, 2019;Wagner et al, 2019). Importantly, kinetochore-association of the motor protein CENP-E was also shown to depend on SUMO homeostasis at centromers (Zhang et al, 2008).…”

“…Loading and maintenance of cohesin in interphase involves the Rad21-associated PDS5A/B protein, although the underlying mechanism is not entirely clear. Data in both higher and lower eukaryotes now suggest that PDS5 at least partly functions by recruitment of a SUMO chain-editing activity to the cohesin core complex (Figure 2A) (Baldwin et al, 2009;Wagner et al, 2019). We detected an association of chromatin-associated PDS5 with SENP6 and found that SENP6 limits the polySUMOylation of PDS5 and all cohesin core components (Wagner et al, 2019).…”

“…Two recent unbiased proteomic screens now confirmed that SENP6 not only counters SUMO chain formation on CENP-I, but also on CENP-H and CENP-K. Moreover, it appears that multiple subunits within all other CCAN subcomplexes undergo unrestricted polySUMOylation in the absence of SENP6 (Liebelt et al, 2019;Wagner et al, 2019). Importantly, in cells lacking SENP6 polySUMOylation of these CCAN components coincides with their loss from centromeres (Liebelt et al, 2019).…”

“…Importantly, in cells lacking SENP6 polySUMOylation of these CCAN components coincides with their loss from centromeres (Liebelt et al, 2019). Surprisingly, polySUMOylation FIGURE 1 | A network of SENP6 targets identified by two recent unbiased proteomic studies (Liebelt et al, 2019;Wagner et al, 2019). Candidate SENP6 targets identified in both studies were combined into a single dataset.…”

“…This is mainly due to the fact that so far the cellular substrates undergoing dynamic polySUMOylation were not well defined. To fill this gap, recent unbiased proteomic screens have focused on the identification of targets for the chain-specific isopeptidase SENP6 (Liebelt et al, 2019;Wagner et al, 2019). To this end alterations in SUMO conjugation were determined following inactivation of SENP6 by siRNA-or shRNA-mediated knock-down.…”