Functional mapping of PHF6 complexes in chromatin remodeling, replication dynamics, and DNA repair
Alvarez Nanez, Silvia (Institute for Cancer Genetics. Columbia University)
da Silva Almeida, Ana C. (Institute for Cancer Genetics. Columbia University)
Albero Gallego, Robert (Institute for Cancer Genetics. Columbia University)
Biswas, M. (Institute for Cancer Genetics. Columbia University)
Barreto-Galvez, A. (Rutgers Cancer Institute of New Jersey)
Gunning, T.S. (Institute for Cancer Genetics. Columbia University)
Shaikh, Anam (Rutgers Cancer Institute of New Jersey)
Aparicio, T. (Institute for Cancer Genetics. Columbia University)
Wendorff, Agnieszka (Institute for Cancer Genetics. Columbia University)
Piovan, Erich (Università di Padova)
Van Vlierberghe, Pieter (Ghent University)
Gygi, Steven (Harvard Medical School. Boston, MA)
Gautier, Jean (Institute for Cancer Genetics. Columbia University)
Madireddy, A. (Rutgers Cancer Institute of New Jersey)
Ferrando, A.A. (Department of Pathology and Cell Biology. Columbia University Irving Medical Center)

Data:	2022
Resum:	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.
Nota:	Altres ajuts: National Institutes of Health, National Cancer Institute (R35 CA210065 and R01 CA155743 ), National Institute on Aging (R01AG077020), and National Cancer Institute grant P30 CA013696
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Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Chromatin ; Chromatin Assembly and Disassembly ; DNA Repair ; Humans ; Leukemia ; Nucleosomes ; Repressor Proteins
Publicat a:	Blood, Vol. 139 Núm. 23 (september 2022) , p. 3418-3429, ISSN 1528-0020

DOI: 10.1182/blood.2021014103
PMID: 35338774

12 p, 1.9 MB

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