Sumoylation Of Hp1 Alpha Supports Association With Ncrna To Define Responsiveness Of Breast Cancer Cells To Chemotherapy
ONCOTARGET(2016)
摘要
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-alpha (HP1 alpha). Canonical models define HP1 alpha as a "reader" of repressive H3K9m3 marks that supports constitutive heterochromatin. It is unclear how SUMOylation affects HP1 alpha function in BCa cells. This report shows HP1 alpha SUMO-dynamics are closely regulated in a complex with SENP7L and SUMO-E3 Polycomb-2 (PC2/CBX4). This complex accumulates at H3K9m3 sites, hypoSUMOylates HP1 alpha and PC2, and reduces PC2's SUMO-E3 activity. HyperSUMO conditions cause complex dissociation, SUMOylation of PC2 and HP1 alpha, and recruitment of SUMOylated HP1 alpha to multiple DNA-repair genes including Rad51C. SUMOylated HP1 alpha's enrichment at euchromatin requires chromatin-bound non-coding RNA (ncRNA), reduces Rad51C protein, and increases DNA-breaks in BCa cells. Hence, HP1 alpha 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 HP1 alpha is a critical epigenetic-regulator of DNA-repair in BCa that could define chemotherapy responsiveness.
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关键词
SUMO, SENP7, HP1 alpha, ncRNA, Rad51C
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