Multinucleation Associated DNA Damage causes quiescence despite compromised p53
Multinucleation Associated DNA Damage causes quiescence despite compromised p53
复制标题
DOI：
10.1101/2020.12.22.424035
复制
发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Madeleine Hart;Sophie D. Adams;Viji M. Draviam
中科院分区：
文献类型：
--
作者：
Madeleine Hart;Sophie D. Adams;Viji M. Draviam
核分裂是癌症进展的最早标志之一。不同形式的细胞核蛋白质如何不同地影响细胞命运在分子水平上还不清楚。在这里，我们进行单细胞跟踪研究，以确定多核或畸形细胞核的直接和长期影响，并揭示多核和微核之间的显着差异，一种灾难性的核分裂，已知促进基因组重排和肿瘤异质性。追踪新生细胞表现出各种核分裂的命运表明，多核化，不像其他形式的核分裂，阻止p53受损细胞的增殖。因为在超过50%的癌症中可以看到受损的p53，我们探索了多核化如何阻止增殖并促进静止。多核化增加了53 BP1修饰的核体（DNA损伤修复平台），沿着多核区室中转录和蛋白质积累的异质性减少。重要的是，多核相关DNA损伤（MADD）相关的53BP1体在几天内仍未得到解决，尽管完整的NHEJ机制可以在几分钟内修复激光诱导的DNA损伤。这种持续的MADD信号传导阻断了DNA复制的开始，并与驱动增殖的G1细胞进入静止状态有关，揭示了由有丝分裂病变引起的新的复制应激无关的细胞周期停滞。这些研究结果要求分离保护性和抑制性核蛋白，以告知旨在限制肿瘤异质性的治疗方法。
Nuclear atypia is one of the earliest hallmarks of cancer progression. How distinct forms of nuclear atypia differently impact cell fate is not understood at the molecular level. Here, we perform single-cell tracking studies to determine the immediate and long-term impact of multinucleation or misshapen nuclei and reveal a significant difference between multinucleation and micronucleation, a catastrophic nuclear atypia known to promote genomic rearrangements and tumour heterogeneity. Tracking the fate of newborn cells exhibiting various nuclear atypia shows that multinucleation, unlike other forms of nuclear atypia, blocks proliferation in p53-compromised cells. Because compromised p53 is seen in over 50% of cancers, we explored how multinucleation blocks proliferation and promotes quiescence. Multinucleation increases 53BP1-decorated nuclear bodies (DNA damage repair platforms), along with a heterogeneous reduction in transcription and protein accumulation across the multi-nucleated compartments. Importantly, Multinucleation Associated DNA Damage (MADD) associated 53BP1-bodies remain unresolved for days, despite an intact NHEJ machinery that repairs laser-induced DNA damage within minutes. This persistent MADD signalling blocks the onset of DNA replication and is associated with driving proliferative G1 cells into quiescence, revealing a novel replication stress independent cell cycle arrest caused by mitotic lesions. These findings call for segregating protective and prohibitive nuclear atypia to inform therapeutic approaches aimed at limiting tumour heterogeneity.