Abstract
In contrast to our extensive knowledge on ubiquitin polymer signaling, we are severely limited in our understanding of poly-SUMO signaling. We set out to identify substrates conjugated to SUMO polymers, using knockdown of the poly-SUMO2/3 protease SENP6. We identify over 180 SENP6 regulated proteins that represent highly interconnected functional groups of proteins including the constitutive centromere-associated network (CCAN), the CENP-A loading factors Mis18BP1 and Mis18A and DNA damage response factors. Our results indicate a striking protein group de-modification by SENP6. SENP6 deficient cells are severely compromised for proliferation, accumulate in G2/M and frequently form micronuclei. Accumulation of CENP-T, CENP-W and CENP-A to centromeres is impaired in the absence of SENP6. Surprisingly, the increase of SUMO chains does not lead to ubiquitin-dependent proteasomal degradation of the CCAN subunits. Our results indicate that SUMO polymers can act in a proteolysis-independent manner and consequently, have a more diverse signaling function than previously expected.
Highlights
In contrast to our extensive knowledge on ubiquitin polymer signaling, we are severely limited in our understanding of poly-SUMO signaling
Knockdown of SENP6 caused an increase in high-molecular weight SUMO2/3 conjugates, but knockdown of SENP7 did not, whereas combined knockdown of both SENP6 and SENP7 caused a stronger increase in SUMO2/3 conjugates (Fig. 1c and Supplementary Fig. 1d)
Since we have shown that SENP6 is responsible for the group deSUMOylation of the centromere-associated network (CCAN) proteins, we wondered if the decreased accumulation of CENP-T and -W at the centromere does apply to the other CCAN components
Summary
In contrast to our extensive knowledge on ubiquitin polymer signaling, we are severely limited in our understanding of poly-SUMO signaling. Two of the three conjugated mammalian SUMO family members, SUMO2 and −3, are able to efficiently form SUMO polymers via internal SUMOylation sites in their flexible Nterminal domains in vitro[12] and in cells[13,14]. These chains are stabilized or increased by cellular stress, such as heat shock[15]. In Saccharomyces cerevisiae SUMO chain formation is regulated by the covalent SUMO attachment to the single SUMO E2 conjugating enzyme, Ubc[9] This activity is counterbalanced by the SUMO specific protease Ulp[2] that is able to disassemble the accumulated SUMO chains[18,19]. SUMO chains contribute to synaptonemal complex formation during meiosis in yeast[18,20] and are required to prevent aneuploidy[21]
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