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

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, et al.
(2022) BLOOD. 139(23). p.3418-3429
Author
Organization
Abstract
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.
Keywords
Cell Biology, Hematology, Immunology, Biochemistry, KAP-1 PHOSPHORYLATION, HEMATOPOIETIC STEM, DAMAGE RESPONSE, FANCONI-ANEMIA, FRAGILE SITES, MUTATIONS, PROTEINS, RECOMBINATION, INSIGHTS, FAILURE

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MLA
Alvarez, Silvia, et al. “Functional Mapping of PHF6 Complexes in Chromatin Remodeling, Replication Dynamics and DNA Repair.” BLOOD, vol. 139, no. 23, 2022, pp. 3418–29, doi:10.1182/blood.2021014103.
APA
Alvarez, S., da Silva Almeida, A., Albero, R., Biswas, M., Barreto-Galvez, A., Gunning, T. S., … Ferrando, A. A. (2022). Functional mapping of PHF6 complexes in chromatin remodeling, replication dynamics and DNA repair. BLOOD, 139(23), 3418–3429. https://doi.org/10.1182/blood.2021014103
Chicago author-date
Alvarez, Silvia, Ana da Silva Almeida, Robert Albero, Mayukh Biswas, Angelica Barreto-Galvez, Thomas S. Gunning, Anam Shaikh, et al. 2022. “Functional Mapping of PHF6 Complexes in Chromatin Remodeling, Replication Dynamics and DNA Repair.” BLOOD 139 (23): 3418–29. https://doi.org/10.1182/blood.2021014103.
Chicago author-date (all authors)
Alvarez, Silvia, 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, and Adolfo A Ferrando. 2022. “Functional Mapping of PHF6 Complexes in Chromatin Remodeling, Replication Dynamics and DNA Repair.” BLOOD 139 (23): 3418–3429. doi:10.1182/blood.2021014103.
Vancouver
1.
Alvarez S, da Silva Almeida A, Albero R, Biswas M, Barreto-Galvez A, Gunning TS, et al. Functional mapping of PHF6 complexes in chromatin remodeling, replication dynamics and DNA repair. BLOOD. 2022;139(23):3418–29.
IEEE
[1]
S. Alvarez et al., “Functional mapping of PHF6 complexes in chromatin remodeling, replication dynamics and DNA repair,” BLOOD, vol. 139, no. 23, pp. 3418–3429, 2022.
@article{8748165,
  abstract     = {{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.}},
  author       = {{Alvarez, Silvia and da Silva Almeida, Ana and Albero, Robert and Biswas, Mayukh and Barreto-Galvez, Angelica and Gunning, Thomas S. and Shaikh, Anam and Aparicio, Tomas and Wendorff, Agnieszka Anya and Piovan, Erich and Van Vlierberghe, Pieter and Gygi, Steven and Gautier, Jean and Madireddy, Advaitha and Ferrando, Adolfo A}},
  issn         = {{0006-4971}},
  journal      = {{BLOOD}},
  keywords     = {{Cell Biology,Hematology,Immunology,Biochemistry,KAP-1 PHOSPHORYLATION,HEMATOPOIETIC STEM,DAMAGE RESPONSE,FANCONI-ANEMIA,FRAGILE SITES,MUTATIONS,PROTEINS,RECOMBINATION,INSIGHTS,FAILURE}},
  language     = {{eng}},
  number       = {{23}},
  pages        = {{3418--3429}},
  title        = {{Functional mapping of PHF6 complexes in chromatin remodeling, replication dynamics and DNA repair}},
  url          = {{http://doi.org/10.1182/blood.2021014103}},
  volume       = {{139}},
  year         = {{2022}},
}
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