TY - JOUR
T1 - Functional mapping of PHF6 complexes in chromatin remodeling, replication dynamics, and DNA repair
AU - Alvarez, Silvia
AU - da Silva Almeida, Ana C.
AU - Albero, Robert
AU - Biswas, Mayukh
AU - Barreto-Galvez, Angelica
AU - Gunning, Thomas S.
AU - Shaikh, Anam
AU - Aparicio, Tomas
AU - Wendorff, Agnieszka
AU - Piovan, Erich
AU - Van Vlierberghe, Pieter
AU - Gygi, Steven
AU - Gautier, Jean
AU - Madireddy, Advaitha
AU - Ferrando, Adolfo A.
N1 - Funding Information:
This work was supported by the National Institutes of Health, National Cancer Institute (R35 CA210065 and R01 CA155743 [A.A.F.]), National Institute on Aging (R01AG077020 [A.A.F.]), and National Cancer Institute grant P30 CA013696 (in support of the Herbert Irving Comprehensive Cancer Center Genomics, Flow Cytometry and Molecular Cytogenetics, Genetically Manipulated Mouse Models, Proteomics and Macromolecular Crystallography, Genomics and High Throughput Screen Shared Resource, and Confocal and Specialized Microscopy Shared Resources). A.W. was supported by a Rally Foundation fellowship. P.V.V. was supported by the Fund for Scientific Research Flanders (postdoctoral fellowship and Odysseus type 2 grant). S.A. was supported by a Leukemia and Lymphoma Society Special Fellowship Award. R.A. was supported by a Leukemia and Lymphoma Society Fellowship Award.
Publisher Copyright:
© 2022 American Society of Hematology
PY - 2022/6/9
Y1 - 2022/6/9
N2 - 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.
AB - 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.
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U2 - 10.1182/blood.2021014103
DO - 10.1182/blood.2021014103
M3 - Article
C2 - 35338774
AN - SCOPUS:85131700113
SN - 0006-4971
VL - 139
SP - 3418
EP - 3429
JO - Blood
JF - Blood
IS - 23
ER -