Oppikofer Mariano, Sagolla Meredith, Haley Benjamin, Zhang Hui-Min, Kummerfeld Sarah K, Sudhamsu Jawahar, Flynn E Megan, Bai Tianyi, Zhang Jennifer, Ciferri Claudio, Cochran Andrea G
Department of Early Discovery Biochemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
Pfizer Worldwide Research and Development, 558 Eastern Point Rd., Groton, CT, 06340, USA.
Nat Commun. 2017 Oct 11;8(1):862. doi: 10.1038/s41467-017-00866-0.
Members of the ISWI family of chromatin remodelers mobilize nucleosomes to control DNA accessibility and, in some cases, are required for recovery from DNA damage. However, it remains poorly understood how the non-catalytic ISWI subunits BAZ1A and BAZ1B might contact chromatin to direct the ATPase SMARCA5. Here, we find that the plant homeodomain of BAZ1A, but not that of BAZ1B, has the unusual function of binding DNA. Furthermore, the BAZ1A bromodomain has a non-canonical gatekeeper residue and binds relatively weakly to acetylated histone peptides. Using CRISPR-Cas9-mediated genome editing we find that BAZ1A and BAZ1B each recruit SMARCA5 to sites of damaged chromatin and promote survival. Genetic engineering of structure-designed bromodomain and plant homeodomain mutants reveals that reader modules of BAZ1A and BAZ1B, even when non-standard, are critical for DNA damage recovery in part by regulating ISWI factors loading at DNA lesions and supporting transcriptional programs required for survival.ISWI chromatin remodelers regulate DNA accessibility and have been implicated in DNA damage repair. Here, the authors uncover functions, in response to DNA damage, for the bromodomain of the ISWI subunit BAZ1B and for the non-canonical PHD and bromodomain modules of the paralog BAZ1A.
染色质重塑因子ISWI家族的成员可移动核小体以控制DNA的可及性，在某些情况下，DNA损伤修复后恢复过程也需要它们。然而，目前仍不清楚非催化性ISWI亚基BAZ1A和BAZ1B如何与染色质接触以指导ATP酶SMARCA5。在这里，我们发现BAZ1A的植物同源结构域具有结合DNA的独特功能，而BAZ1B的植物同源结构域则没有。此外，BAZ1A的溴结构域具有一个非典型的守门残基，并且与乙酰化组蛋白肽的结合相对较弱。使用CRISPR-Cas9介导的基因组编辑，我们发现BAZ1A和BAZ1B均可将SMARCA5募集到受损染色质位点并促进细胞存活。对结构设计的溴结构域和植物同源结构域突变体进行基因工程改造后发现，BAZ1A和BAZ1B的读取模块即使是非标准的，对于DNA损伤修复也至关重要，部分原因是它们可调节ISWI因子在DNA损伤位点的加载，并支持细胞存活所需的转录程序。ISWI染色质重塑因子可调节DNA的可及性，并与DNA损伤修复有关。在这里，作者揭示了ISWI亚基BAZ1B的溴结构域以及旁系同源物BAZ1A的非典型植物同源结构域（PHD）和溴结构域模块在应对DNA损伤时的功能。
