Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Illkirch, France; Centre National de Recherche Scientifique (CNRS), UMR7104, Illkirch, France; Université de Strasbourg, Illkirch, France.
School of Physics, University of Melbourne, Melbourne, VIC, Australia.
Mol Cell. 2022 Jun 2;82(11):2132-2147.e6. doi: 10.1016/j.molcel.2022.03.033. Epub 2022 Apr 20.
Mouse pericentromeric DNA is composed of tandem major satellite repeats, which are heterochromatinized and cluster together to form chromocenters. These clusters are refractory to DNA repair through homologous recombination (HR). The mechanisms by which pericentromeric heterochromatin imposes a barrier on HR and the implications of repeat clustering are unknown. Here, we compare the spatial recruitment of HR factors upon double-stranded DNA breaks (DSBs) induced in human and mouse pericentromeric heterochromatin, which differ in their capacity to form clusters. We show that while DSBs increase the accessibility of human pericentromeric heterochromatin by disrupting HP1α dimerization, mouse pericentromeric heterochromatin repeat clustering imposes a physical barrier that requires many layers of de-compaction to be accessed. Our results support a model in which the 3D organization of heterochromatin dictates the spatial activation of DNA repair pathways and is key to preventing the activation of HR within clustered repeats and the onset of chromosomal translocations.
鼠着丝粒 DNA 由串联的主要卫星重复序列组成，这些重复序列异染色质化并聚集在一起形成着丝粒中心。这些簇对同源重组 (HR) 的 DNA 修复具有抗性。着丝粒异染色质对 HR 施加障碍的机制以及重复序列聚集的影响尚不清楚。在这里，我们比较了在人类和小鼠着丝粒异染色质中诱导双链 DNA 断裂 (DSB) 时 HR 因子的空间募集情况，这两种情况在形成簇的能力上有所不同。我们表明，虽然 DSB 通过破坏 HP1α 二聚化增加了人类着丝粒异染色质的可及性，但小鼠着丝粒异染色质重复序列的聚集形成了物理障碍，需要多层解压缩才能进入。我们的结果支持这样一种模型，即异染色质的 3D 组织决定了 DNA 修复途径的空间激活，这对于防止在聚集的重复序列中激活 HR 和染色体易位的发生至关重要。
