Functional mapping of PHF6 complexes in chromatin remodeling, replication dynamics, and DNA repair

• Published in: Blood Vol. 139; no. 23; pp. 3418 - 3429
• Main Authors: Alvarez, Silvia, da Silva Almeida, Ana C., Albero, Robert, Biswas, Mayukh, Barreto-Galvez, Angelica, Gunning, Thomas S., Shaikh, Anam, Aparicio, Tomas, Wendorff, Agnieszka, Piovan, Erich, Van Vlierberghe, Pieter, Gygi, Steven, Gautier, Jean, Madireddy, Advaitha, Ferrando, Adolfo A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.06.2022; American Society of Hematology
• Subjects: Chromatin - genetics; Chromatin Assembly and Disassembly; DNA Repair; Humans; Leukemia; Lymphoid Neoplasia; Nucleosomes; Repressor Proteins - genetics; Repressor Proteins - metabolism
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2021014103

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 nucleosome remodeling and deacetylase, SWI/SNF and ISWI factors, the replication machinery and DNA repair proteins. Moreover, after 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-strand DNA lesions. Native chromatin immunoprecipitation sequencing analyses show that PHF6 specifically associates with difficult-to-replicate heterochromatin at satellite DNA regions enriched in histone H3 lysine 9 trimethyl marks, 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 hematopoietic stem cell homeostasis and leukemia transformation by placing PHF6 at the crossroads of chromatin remodeling, replicative fork dynamics, and DNA repair. •PHF6 interacts with NurD, SWI/SNF and ISWI factors, the replication machinery, and DNA repair proteins.•PHF6 associates with heterochromatin at satellite DNA and protects genomic fragile sites from DNA damage–induced genetic instability. [Display omitted]