生物
着丝粒
复制(统计)
基因组
遗传学
DNA复制
计算生物学
人类基因组
细胞生物学
DNA
染色体
基因
病毒学
作者
Andrea Scelfo,Annapaola Angrisani,Marco Grillo,Bethany M. Barnes,Francesc Muyas,Carolin M. Sauer,Chi Hung Leung,Marie Dumont,Marine Grison,David Mazaud,Mickaël Garnier,Laetitia Guintini,Louisa Nelson,Fumiko Esashi,Isidro Cortés-Ciriano,Stephen S. Taylor,Jérôme Déjardin,Thérèse Wilhelm,Daniele Fachinetti
出处
期刊:Molecular Cell
[Elsevier]
日期:2024-03-01
卷期号:84 (6): 1003-1020.e10
标识
DOI:10.1016/j.molcel.2024.01.018
摘要
Summary
The high incidence of whole-arm chromosome aneuploidy and translocations in tumors suggests instability of centromeres, unique loci built on repetitive sequences and essential for chromosome separation. The causes behind this fragility and the mechanisms preserving centromere integrity remain elusive. We show that replication stress, hallmark of pre-cancerous lesions, promotes centromeric breakage in mitosis, due to spindle forces and endonuclease activities. Mechanistically, we unveil unique dynamics of the centromeric replisome distinct from the rest of the genome. Locus-specific proteomics identifies specialized DNA replication and repair proteins at centromeres, highlighting them as difficult-to-replicate regions. The translesion synthesis pathway, along with other factors, acts to sustain centromere replication and integrity. Prolonged stress causes centromeric alterations like ruptures and translocations, as observed in ovarian cancer models experiencing replication stress. This study provides unprecedented insights into centromere replication and integrity, proposing mechanistic insights into the origins of centromere alterations leading to abnormal cancerous karyotypes.
科研通智能强力驱动
Strongly Powered by AbleSci AI