染色质重塑
生物
染色质
DNA修复
细胞生物学
组蛋白
核小体
DNA复制
异染色质
遗传学
作者
Silvia Alvarez,Ana da Silva Almeida,Robert Albero,Mayukh Biswas,Angelica Barreto-Galvez,Thomas S Gunning,Anam Shaikh,Tomas Aparicio,Agnieszka Anya Wendorff,Erich Piovan,Pieter Van Vlierberghe,Steven Gygi,Jean Gautier,Advaitha Madireddy,Adolfo A Ferrando
出处
期刊:Blood
[American Society of Hematology]
日期:2022-03-25
标识
DOI:10.1182/blood.2021014103
摘要
The Plant Homeodomain 6 gene (PHF6) encodes a nucleolar and chromatin-associated leukemia tumor suppressor with proposed roles in transcription regulation. However, specific molecular mechanisms controlled by PHF6 remain rudimentarily understood. Here we show that PHF6 engages multiple nucleosome remodeling protein complexes including NuRD, SWI/SNF and ISWI factors, the replication machinery and DNA repair proteins. Moreover, following DNA damage, PHF6 localizes to sites of DNA injury and its loss impairs the resolution of DNA breaks with consequent accumulation of single- and double-stranded DNA lesions. Native chromatin immunoprecipitation sequencing analyses reveal that PHF6 specifically associates with difficult to replicate heterochromatin at satellite DNA regions enriched in Histone H3 lysine 9 trimethyl marks (H3K9me3) and single molecule locus-specific analyses identify PHF6 as an important regulator of genomic stability at fragile sites. These results extend our understanding of the molecular mechanisms controlling HSC homeostasis and leukemia transformation by placing PHF6 at the crossroads of chromatin remodeling, replicative fork dynamics and DNA repair.
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