Bantele Susanne Cs, Ferreira Pedro, Gritenaite Dalia, Boos Dominik, Pfander Boris
DNA Replication and Genome Integrity, Max Planck Institute of Biochemistry, Martinsried, Germany.
Centre for Medical Biotechnology, Molecular Genetics II, University Duisburg-Essen, Essen, Germany.
Elife. 2017 Jan 12;6:e21687. doi: 10.7554/eLife.21687.
DNA double strand breaks (DSBs) can be repaired by either recombination-based or direct ligation-based mechanisms. Pathway choice is made at the level of DNA end resection, a nucleolytic processing step, which primes DSBs for repair by recombination. Resection is thus under cell cycle control, but additionally regulated by chromatin and nucleosome remodellers. Here, we show that both layers of control converge in the regulation of resection by the evolutionarily conserved Fun30/SMARCAD1 remodeller. Budding yeast Fun30 and human SMARCAD1 are cell cycle-regulated by interaction with the DSB-localized scaffold protein Dpb11/TOPBP1, respectively. In yeast, this protein assembly additionally comprises the 9-1-1 damage sensor, is involved in localizing Fun30 to damaged chromatin, and thus is required for efficient long-range resection of DSBs. Notably, artificial targeting of Fun30 to DSBs is sufficient to bypass the cell cycle regulation of long-range resection, indicating that chromatin remodelling during resection is underlying DSB repair pathway choice.
DNA双链断裂（DSBs）可通过基于重组或基于直接连接的机制进行修复。修复途径的选择在DNA末端切除水平进行，这是一个核酸酶处理步骤，它启动了通过重组修复DSBs的过程。因此，切除受细胞周期控制，但还受到染色质和核小体重塑因子的调节。在这里，我们表明这两层控制在进化上保守的Fun30/SMARCAD1重塑因子对切除的调节中汇聚。芽殖酵母Fun30和人类SMARCAD1分别通过与DSB定位的支架蛋白Dpb11/TOPBP1相互作用而受到细胞周期调节。在酵母中，这种蛋白质组装还包括9-1-1损伤传感器，参与将Fun30定位到受损染色质上，因此是DSBs高效长距离切除所必需的。值得注意的是，将Fun30人工靶向到DSBs足以绕过细胞周期对长距离切除的调节，这表明切除过程中的染色质重塑是DSB修复途径选择的基础。
