奥地利科学院CeMM分子医学研究中心Stefan Kubicek研究团队，通过系统性对BAF复合物不同亚单位进行突变，揭示了合成致死效应，为研究癌症提供了新视角。这一研究成果于8月19日在线发表在国际学术期刊《自然—遗传学》上。

该课题组研究人员构建了BAF复合物22个亚基逐一敲除的细胞系，从而研究单个亚基丢失对整个复合物组成、染色质可及性和基因表达的影响。研究人员观察到依赖于目标亚基的强烈、特异、有时不协调的改变，并表明这些改变可以解释复合物不同亚基间的相互依赖性，这包括SMARCA4-ARID2、SMARCA4-ACTB和SMARCC1-SMARCC2合成致死互作。该研究为了解不同的BAF亚单位在全基因组染色质组织中的作用提供了见解，并为针对BAF突变癌症的靶向治疗提供了方法。

据了解，在人类癌症中，编码BRG1/BRM相关因子（BAF）染色质重塑复合物亚基的基因突变非常丰富。目前，人们尚不清楚这些主要功能丧失的突变如何促进癌症的发展以及这些突变能否用于癌症的靶向治疗。特定亚基突变导致特定癌症发生的模式，提示特定亚基异常可能是通过形成异常残留复合物从而影响BAF复合物的功能。

附：英文原文

Title: Systematic characterization of BAF mutations provides insights into intracomplex synthetic lethalities in human cancers

Author: Sandra Schick, André F. Rendeiro, Kathrin Runggatscher, Anna Ringler, Bernd Boidol, Melanie Hinkel, Peter Májek, Loan Vulliard, Thomas Penz, Katja Parapatics, Christian Schmidl, Jörg Menche, Guido Boehmelt, Mark Petronczki, André C. Müller, Christoph Bock, Stefan Kubicek 

Issue&Volume: 19 August 2019

Abstract: Aberrations in genes coding for subunits of the BRG1/BRM associated factor (BAF) chromatin remodeling complexes are highly abundant in human cancers. Currently, it is not understood how these mostly loss-of-function mutations contribute to cancer development and how they can be targeted therapeutically. The cancer-type-specific occurrence patterns of certain subunit mutations suggest subunit-specific effects on BAF complex function, possibly by the formation of aberrant residual complexes. Here, we systematically characterize the effects of individual subunit loss on complex composition, chromatin accessibility and gene expression in a panel of knockout cell lines deficient for 22 BAF subunits. We observe strong, specific and sometimes discordant alterations dependent on the targeted subunit and show that these explain intracomplex codependencies, including the synthetic lethal interactions SMARCA4–ARID2, SMARCA4–ACTB and SMARCC1–SMARCC2. These data provide insights into the role of different BAF subcomplexes in genome-wide chromatin organization and suggest approaches to therapeutically target BAF-mutant cancers.

DOI: https://doi.org/10.1038/s41588-019-0477-9

Source: https://www.nature.com/articles/s41588-019-0477-9