Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269, USA.
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
J Cell Sci. 2023 Jan 1;136(1). doi: 10.1242/jcs.260027. Epub 2023 Jan 6.
53BP1 (also known as TP53BP1) is a key mediator of the non-homologous end joining (NHEJ) DNA repair pathway, which is the primary repair pathway in interphase cells. However, the mitotic functions of 53BP1 are less well understood. Here, we describe 53BP1 mitotic stress bodies (MSBs) formed in cancer cell lines in response to delayed mitosis. These bodies displayed liquid-liquid phase separation characteristics, were close to centromeres, and included lamin A/C and the DNA repair protein RIF1. After release from mitotic arrest, 53BP1 MSBs decreased in number and moved away from the chromatin. Using GFP fusion constructs, we found that the 53BP1 oligomerization domain region was required for MSB formation, and that inclusion of the 53BP1 N terminus increased MSB size. Exogenous expression of 53BP1 did not increase MSB size or number but did increase levels of MSB-free 53BP1. This was associated with slower mitotic progression, elevated levels of DNA damage and increased apoptosis, which is consistent with MSBs suppressing a mitotic surveillance by 53BP1 through sequestration. The 53BP1 MSBs, which were also found spontaneously in a subset of normally dividing cancer cells but not in non-transformed cells (ARPE-19), might facilitate the survival of cancer cells following aberrant mitoses. This article has an associated First Person interview with the first author of the paper.
53BP1（也称为 TP53BP1）是非同源末端连接（NHEJ）DNA 修复途径的关键介质，该途径是间期中细胞的主要修复途径。然而，53BP1 的有丝分裂功能了解较少。在这里，我们描述了癌细胞系中延迟有丝分裂后形成的 53BP1 有丝分裂应激体（MSB）。这些体显示出液-液相分离的特征，靠近着丝粒，并包括核纤层 A/C 和 DNA 修复蛋白 RIF1。从有丝分裂阻滞中释放后，53BP1 MSB 的数量减少并远离染色质。使用 GFP 融合构建体，我们发现 53BP1 寡聚化结构域区域是形成 MSB 的必需条件，并且包含 53BP1 N 端会增加 MSB 的大小。外源性表达 53BP1 不会增加 MSB 的大小或数量，但会增加 MSB 游离 53BP1 的水平。这与有丝分裂进展缓慢、DNA 损伤水平升高和细胞凋亡增加有关，这与 MSB 通过隔离来抑制 53BP1 的有丝分裂监测一致。在一小部分正常分裂的癌细胞中自发发现的 53BP1 MSB 而不是非转化细胞（ARPE-19）中没有发现，这可能有助于癌细胞在异常有丝分裂后存活。本文有该论文第一作者的相关第一人称采访。
