Abstract
Epigenetic reprogramming allows cancer cells to bypass normal checkpoints and potentiate aberrant proliferation. Several chromatin regulators are subject to reversible SUMO-modification but little is known about how SUMOylation of chromatin-remodelers modulates the cancer epigenome. Recently, we demonstrated that SUMO-protease SENP7L is upregulated in aggressive BCa and maintains hypoSUMOylated heterochromatin protein 1-α (HP1α). Canonical models define HP1α as a “reader” of repressive H3K9m3 marks that supports constitutive heterochromatin. It is unclear how SUMOylation affects HP1α function in BCa cells. This report shows HP1α SUMO-dynamics are closely regulated in a complex with SENP7L and SUMO-E3 Polycomb-2 (PC2/CBX4). This complex accumulates at H3K9m3 sites, hypoSUMOylates HP1α and PC2, and reduces PC2's SUMO-E3 activity. HyperSUMO conditions cause complex dissociation, SUMOylation of PC2 and HP1α, and recruitment of SUMOylated HP1α to multiple DNA-repair genes including Rad51C. SUMOylated HP1α's enrichment at euchromatin requires chromatin-bound non-coding RNA (ncRNA), reduces Rad51C protein, and increases DNA-breaks in BCa cells. Hence, HP1α SUMOylation and consistently low SENP7L increase efficacy of DNA-damaging chemotherapeutic agents. BCa patients on chemotherapy that express low SENP7L exhibit greater survival rates than patients with high SENP7L. Collectively, these studies suggest that SUMOylated HP1α is a critical epigenetic-regulator of DNA-repair in BCa that could define chemotherapy responsiveness.
Highlights
SUMO post-translational modification (PTM) of protein substrates is important for normal cell physiology but is thrown off kilter with the onset of cancer [1, 2]
Since PC2 interacts with H3K9m3 sites, we postulated that overexpression of this SUMO E3 ligase would potentiate SUMO-PTM of heterochromatin protein 1-α (HP1α)
SIM2 overlaps with a canonical HP1α-interaction motif (HIM), which supports PC2 binding to HP1α
Summary
SUMO post-translational modification (PTM) of protein substrates is important for normal cell physiology but is thrown off kilter with the onset of cancer [1, 2]. This process or SUMOylation requires one or more of 3 SUMO isoforms, E1 activating molecules, and a sole E2 conjugating enzyme Ubc. Often SUMO E3 ligases facilitate interaction between Ubc and the target protein and thereby potentiate the conjugation reaction. SUMO E3 ligase Polycomb-2 (PC2/ CBX4) can associate with H3K9m3 and an additional repressive mark tri-methylated histone 3 lysine 27 residue (H3K27m3) as established in recombinant in vitro systems [8]. Enrichment of SENP7L to H3K9m3 requires interaction with the canonical H3K9m3 reader heterochromatin protein-1 alpha (HP1α)
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