Fanconi贫血途径诱导染色体碎裂和ecDNA驱动的癌症药物抗性

The Fanconi anemia pathway induces chromothripsis and ecDNA-driven cancer drug resistance

CELL

影响因子:42.5

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

DOI: 10.1016/j.cell.2024.08.001

摘要

染色体碎裂（chromothripsis）描述了错配分离的染色体被困在微核中发生灾难性破碎的现象。尽管微核在整个间期累积DNA双链断裂和复制缺陷，但染色体碎裂的具体机制仍未明晰。通过CRISPR-Cas9筛选，我们发现Fanconi贫血（FA）途径具有非经典的驱动染色体碎裂的作用。FA途径失活抑制了有丝分裂期间的染色体碎裂，但不影响微核中的间期相关缺陷。FA核心复合物促使FANCI-FANCD2单泛素化，从而在有丝分裂中与未完全复制的微核染色体结合。结构选择性核酶SLX4-XPF-ERCC1随后介导对持续复制中间体的大规模核酸酶切割，诱导依赖POLD3的有丝分裂DNA合成，为碎裂片段的再组装提供前期条件。值得注意的是，FA途径引发的染色体碎裂产生复杂的基因组重排和环状DNA，赋予癌细胞对抗癌药物的获得性抗性。我们的研究揭示了一个矛盾的机制：中心DNA修复机制的异常激活，反而通过染色体碎裂推动癌基因组的演化。

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.