Human UBN1 Is an Ortholog of Yeast Hpc2p and Has an Essential Role in the HIRA/ASF1a Chromatin-Remodeling Pathway in Senescent Cells
Human UBN1 Is an Ortholog of Yeast Hpc2p and Has an Essential Role in the HIRA/ASF1a Chromatin-Remodeling Pathway in Senescent Cells
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DOI：
10.1128/mcb.01047-08
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发表时间：
2009-02-01
影响因子：
5.3
通讯作者：
Adams, Peter D.
中科院分区：
文献类型：
--
作者：
Banumathy, Gowrishankar;Somaiah, Neeta;Adams, Peter D.
细胞衰老（Cellular senescence）是一种不可逆的增殖停滞、肿瘤抑制过程，并且可能是组织衰老的原因。衰老通常以兼性异染色质区域为特征，这些区域被称为衰老相关异染色质灶（senescence - associated heterochromatin foci，SAHF），它们抑制促进增殖的基因的表达。鉴于其可能对肿瘤抑制和组织衰老有作用，确定SAHF组装途径的所有成分至关重要。人类细胞中SAHF的形成是由一组组蛋白伴侣复合物驱动的，即HIRA和ASF1a。在酵母中，与HIRA/ASF1a同源的复合物包含另外两种蛋白质，Hpc2p和Hir3p。通过一种复杂的方法来寻找在进化过程中多个物种中保守的远同源物，我们确定了与HIRA相关的蛋白质UBN1和UBN2是Hpc2p的候选人类同源物。我们表明UBN1、UBN2和Hpc2p的与Hpc2相关的结构域是一个在进化上保守的HIRA/Hir结合结构域，它直接与HIRA/Hir的N末端WD重复序列相互作用。UBN1与被SAHF抑制的促进增殖的基因结合，并与组蛋白甲基转移酶活性相关联，该酶活性使组蛋白H3的赖氨酸9甲基化，这是在SAHF中被甲基化的位点。UBN1对于SAHF的形成是必不可少的。我们得出结论，UBN1是酵母Hpc2p的同源物，并且是一种新的衰老调节因子。
Cellular senescence is an irreversible proliferation arrest, tumor suppression process and likely contributor to tissue aging. Senescence is often characterized by domains of facultative heterochromatin, called senescence-associated heterochromatin foci (SAHF), which repress expression of proliferation-promoting genes. Given its likely contribution to tumor suppression and tissue aging, it is essential to identify all components of the SAHF assembly pathway. Formation of SAHF in human cells is driven by a complex of histone chaperones, namely, HIRA and ASF1a. In yeast, the complex orthologous to HIRA/ASF1a contains two additional proteins, Hpc2p and Hir3p. Using a sophisticated approach to search for remote orthologs conserved in multiple species through evolution, we identified the HIRA-associated proteins, UBN1 and UBN2, as candidate human orthologs of Hpc2p. We show that the Hpc2-related domain of UBN1, UBN2, and Hpc2p is an evolutionarily conserved HIRA/Hir-binding domain, which directly interacts with the N-terminal WD repeats of HIRA/Hir. UBN1 binds to proliferation-promoting genes that are repressed by SAHF and associates with histone methyltransferase activity that methylates lysine 9 of histone H3, a site that is methylated in SAHF. UBN1 is indispensable for formation of SAHF. We conclude that UBN1 is an ortholog of yeast Hpc2p and a novel regulator of senescence.