Fanconi贫血途径诱导了铬骨和ECDNA驱动的癌症耐药性
The Fanconi anemia pathway induces chromothripsis and ecDNA-driven cancer drug resistance
影响因子:42.50000
分区:生物学1区 Top / 生化与分子生物学1区 细胞生物学1区
发表日期:2024 Oct 17
作者:
Justin L Engel, Xiao Zhang, Mingming Wu, Yan Wang, Jose Espejo Valle-Inclán, Qing Hu, Kidist S Woldehawariat, Mathijs A Sanders, Agata Smogorzewska, Jin Chen, Isidro Cortés-Ciriano, Roger S Lo, Peter Ly
摘要
染色体描述了被困在微核中的错误分离的染色体的灾难性破碎。尽管微核会累积DNA双链断裂和整个相间的复制缺陷，但染色体如何崩溃仍未解决。使用CRISPR-CAS9屏幕，我们确定了Fanconi贫血（FA）途径的非典型作用，作为Chromothripsis的驱动力。 FA途径的灭活会抑制有丝分裂过程中染色体破碎的，而不会影响微核中与相间相关的缺陷。 FA核心复合物对FANCI-FANCD2的单素化促进了其与复制不足的微核染色体的有丝分裂互动。结构选择性的SLX4-XPF-ERCC1内切核酸酶随后诱导持续的DNA复制中间体的大规模核酸化裂解，从而刺激Pold3依赖性有丝分裂DNA合成以在随后的细胞周期中重新组装质量损坏。值得注意的是，FA-Pathway诱导的Chromothripsis会产生复杂的基因组重排和外骨外DNA，从而赋予对抗癌疗法的耐药性。我们的发现表明了中央DNA修复机制的病理激活如何矛盾地触发通过染色体的癌症基因组进化。
Abstract
Chromothripsis describes the catastrophic shattering of mis-segregated chromosomes trapped within micronuclei. Although micronuclei accumulate DNA double-strand breaks and replication defects throughout interphase, how chromosomes undergo shattering remains unresolved. Using CRISPR-Cas9 screens, we identify a non-canonical role of the Fanconi anemia (FA) pathway as a driver of chromothripsis. Inactivation of the FA pathway suppresses chromosome shattering during mitosis without impacting interphase-associated defects within micronuclei. Mono-ubiquitination of FANCI-FANCD2 by the FA core complex promotes its mitotic engagement with under-replicated micronuclear chromosomes. The structure-selective SLX4-XPF-ERCC1 endonuclease subsequently induces large-scale nucleolytic cleavage of persistent DNA replication intermediates, which stimulates POLD3-dependent mitotic DNA synthesis to prime shattered fragments for reassembly in the ensuing cell cycle. Notably, FA-pathway-induced chromothripsis generates complex genomic rearrangements and extrachromosomal DNA that confer acquired resistance to anti-cancer therapies. Our findings demonstrate how pathological activation of a central DNA repair mechanism paradoxically triggers cancer genome evolution through chromothripsis.