Martin Franck, Kazrani Asgar Abbas, Lafouge Julie, Diaz-Jimenez Dana Mariel, Siebert Stéphanie, Fabbro-Burtschell Leonie, Maillard Emma, Lapouge Karine, Mertens Haydyn David Thomas, Sauter Claude, Leitner Alexander, Ochsenbein Françoise, Blais Alexandre, Bergamin Elisa
Department of Functional Genomics and Cancer & Department of Integrated Structural Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67400 Illkirch-Graffenstaden, France.
Université de Strasbourg, 67084 Strasbourg, France.
Nucleic Acids Res. 2025 Apr 10;53(7). doi: 10.1093/nar/gkaf273.
Proteins of the BCL7 family (BCL7A, BCL7B, and BCL7C) are among the most recently identified subunits of the mammalian SWI/SNF chromatin remodeler complex and are absent from the unicellular version of this complex. Their function in the complex is unknown, and very limited structural information is available, despite the fact that they are mutated in several cancer types, most notably blood malignancies and hence medically relevant. Here, using cryo-electron microscopy in combination with biophysical and biochemical approaches, we show that BCL7A forms a stable, high-affinity complex with the nucleosome core particle (NCP) through binding of BCL7A with the acidic patch of the nucleosome via an arginine anchor motif. This interaction is impaired by BCL7A mutations found in cancer. Further, we determined that BCL7A contributes to the remodeling activity of the mSWI/SNF complex and we examined its function at the genomic level. Our findings reveal how BCL7 proteins interact with the NCP and help rationalize the impact of cancer-associated mutations. By providing structural information on the positioning of BCL7 on the NCP, our results broaden the understanding of the mechanism by which SWI/SNF recognizes the chromatin fiber.
BCL7家族的蛋白质(BCL7A、BCL7B和BCL7C)是哺乳动物SWI/SNF染色质重塑复合物中最近才被鉴定出来的亚基,在该复合物的单细胞版本中不存在。它们在复合物中的功能尚不清楚,尽管它们在几种癌症类型中发生了突变,最显著的是血液系统恶性肿瘤,因此具有医学相关性,但目前可获得的结构信息非常有限。在这里,我们结合使用冷冻电子显微镜以及生物物理和生化方法,表明BCL7A通过其精氨酸锚定基序与核小体的酸性区域结合,从而与核小体核心颗粒(NCP)形成稳定的高亲和力复合物。癌症中发现的BCL7A突变会损害这种相互作用。此外,我们确定BCL7A有助于mSWI/SNF复合物的重塑活性,并在基因组水平上研究了其功能。我们的研究结果揭示了BCL7蛋白如何与NCP相互作用,并有助于解释癌症相关突变的影响。通过提供关于BCL7在NCP上定位的结构信息,我们的结果拓宽了对SWI/SNF识别染色质纤维机制的理解。