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首页> 外文期刊>Molecular and Cellular Biology >BRG1 Is Required for Formation of Senescence-Associated Heterochromatin Foci Induced by Oncogenic RAS or BRCA1 Loss
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BRG1 Is Required for Formation of Senescence-Associated Heterochromatin Foci Induced by Oncogenic RAS or BRCA1 Loss

机译：致癌RAS或BRCA1丢失诱导衰老相关的异染色质病灶形成需要BRG1。

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Cellular senescence is an important tumor suppression mechanism. We have previously reported that both oncogene-induced dissociation of BRCA1 from chromatin and BRCA1 knockdown itself drive senescence by promoting formation of senescence-associated heterochromatin foci (SAHF). However, the molecular mechanism by which BRCA1 regulates SAHF formation and senescence is unclear. BRG1 is a chromatin-remodeling factor that interacts with BRCA1 and pRB. Here we show that BRG1 is required for SAHF formation and senescence induced by oncogenic RAS or BRCA1 loss. The interaction between BRG1 and BRCA1 is disrupted during senescence. This correlates with an increased level of chromatin-associated BRG1 in senescent cells. BRG1 knockdown suppresses the formation of SAHF and senescence, while it has no effect on BRCA1 chromatin dissociation induced by oncogenic RAS, indicating that BRG1 functions downstream of BRCA1 chromatin dissociation. Furthermore, BRG1 knockdown inhibits SAHF formation and senescence induced by BRCA1 knockdown. Conversely, BRG1 overexpression drives SAHF formation and senescence in a DNA damage-independent manner. This effect depends upon BRG1's chromatin-remodeling activity as well as the interaction between BRG1 and pRB. Indeed, the interaction between BRG1 and pRB is enhanced during senescence. Chromatin immunoprecipitation analysis revealed that BRG1's association with the human CDKN2A and CDKN1A gene promoters was enhanced during senescence induced by oncogenic RAS or BRCA1 knockdown. Consistently, knockdown of pRB, p21CIP1, and p16INK4a, but not p53, suppressed SAHF formation induced by BRG1. Together, these studies reveal the molecular underpinning by which BRG1 acts downstream of BRCA1 to promote SAHF formation and senescence.
机译：细胞衰老是重要的肿瘤抑制机制。我们以前曾报道过，癌基因诱导的BRCA1从染色质解离和BRCA1敲低本身都通过促进衰老相关异染色质病灶（SAHF）的形成来驱动衰老。但是，BRCA1调节SAHF形成和衰老的分子机制尚不清楚。 BRG1是与BRCA1和pRB相互作用的染色质重塑因子。在这里，我们显示BRG1是由致癌RAS或BRCA1丢失诱导SAHF形成和衰老所必需的。 BRG1和BRCA1之间的相互作用在衰老过程中被破坏。这与衰老细胞中与染色质相关的BRG1水平升高有关。 BRG1组合式抑制SAHF的形成和衰老，而对致癌RAS诱导的BRCA1染色质解离没有影响，表明BRG1在BRCA1染色质解离的下游起作用。此外，BRG1敲低抑制由BRCA1敲低引起的SAHF形成和衰老。相反，BRG1过表达以DNA损伤独立的方式驱动SAHF的形成和衰老。这种作用取决于BRG1的染色质重塑活性以及BRG1与pRB之间的相互作用。实际上，BRG1和pRB之间的相互作用在衰老过程中得到了增强。染色质免疫沉淀分析表明，BRG1与人 CDKN2A 和 CDKN1A 基因启动子的关联在致癌RAS或BRCA1敲低引起的衰老过程中得到增强。一致地，pRB，p21 CIP1 和p16 INK4a （而非p53）的敲低抑制了BRG1诱导的SAHF形成。总之，这些研究揭示了BRG1在BRCA1下游起作用以促进SAHF形成和衰老的分子基础。

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