Functional mapping of PHF6 complexes in chromatin remodeling, replication dynamics and DNA repair
- Author
- 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 (UGent) , Steven Gygi, Jean Gautier, Advaitha Madireddy and Adolfo A Ferrando
- 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
Downloads
-
blood.2021014103.pdf
- full text (Accepted manuscript)
- |
- open access
- |
- |
- 6.09 MB
Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-8748165
- 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}}, }
- Altmetric
- View in Altmetric
- Web of Science
- Times cited: