SENP6

SENP6 (SUMO-specific protease 6) is a cysteine protease in the SENP family that removes SUMO (Small Ubiquitin-like Modifier) from target proteins. In humans, SENP6 shows a strong preference for SUMO2 and SUMO3, efficiently deconjugating SUMO2/3 from substrates and hydrolyzing poly-SUMO chains, with comparatively weaker activity toward SUMO1. This activity contributes to reversing SUMOylation and limiting chain elongation on proteins.

Biochemically, SENP6 contains a catalytic domain characteristic of Ulp/SENP family proteases and uses a cysteine protease mechanism to cleave isopeptide bonds linking SUMO to lysine residues. Its specificity for SUMO2/3 rather than SUMO1 underpins its role in editing poly-SUMO conjugates and shaping SUMO signaling in the cell.

Cellularly, SENP6 is predominantly localized to the nucleus and is involved in chromatin regulation and maintenance of genome stability. It participates in the DNA damage response and modulates SUMOylation on chromatin-associated factors, including components of the SMC5/6 complex, which are important for DNA repair and chromosome maintenance.

Functional consequences of SENP6 activity include preventing excessive SUMO2/3 chain accumulation and preserving proper chromatin dynamics. Loss or reduction of SENP6 leads to increased SUMO2/3 conjugation, replication stress, and chromosomal abnormalities in model systems, highlighting its essential role in nuclear SUMO homeostasis.

SENP6 is expressed broadly across tissues, consistent with a housekeeping function in regulating SUMOylation status. Dysregulation of SENP6-mediated deSUMOylation can influence chromatin behavior and cellular responses to DNA damage, with potential implications in cancer biology and genome maintenance.