@article{5f3d473da7a349ceafe7df6eb29e894d,
title = "PHF6 promotes non-homologous end joining and G2 checkpoint recovery",
abstract = "The cellular response to DNA breaks is influenced by chromatin compaction. To identify chromatin regulators involved in the DNA damage response, we screened for genes that affect recovery following DNA damage using an RNAi library of chromatin regulators. We identified genes involved in chromatin remodeling, sister chromatid cohesion, and histone acetylation not previously associated with checkpoint recovery. Among these is the PHD finger protein 6 (PHF6), a gene mutated in B{\"o}rjeson–Forssman–Lehmann syndrome and leukemic cancers. We find that loss of PHF6 dramatically compromises checkpoint recovery in G2 phase cells. Moreover, PHF6 is rapidly recruited to sites of DNA lesions in a PARP-dependent manner and required for efficient DNA repair through classical non-homologous end joining. These results indicate that PHF6 is a novel DNA damage response regulator that promotes end joining-mediated repair, thereby stimulating timely recovery from the G2 checkpoint.",
keywords = "checkpoint recovery, chromatin regulators, NHEJ, PHF6, siRNA screen",
author = "Warmerdam, \{Dani{\"e}l O.\} and \{Alonso-de Vega\}, Ignacio and Wiegant, \{Wouter W.\} and \{van den Broek\}, Bram and Rother, \{Magdalena B.\} and Wolthuis, \{Rob M.F.\} and Raimundo Freire and \{van Attikum\}, Haico and Medema, \{Ren{\'e} H.\} and Smits, \{Veronique A.J.\}",
note = "Funding Information: We thank Jozef G{\'e}cz for sharing GFP-PHF6, Susan Janicki for YFP-BRD2, Thijn Brummelkamp for the pTIA-Puro vector, Feng Zhang for pX458 (Addgene plasmid \#48138), and Bernard Lopes for the GC92 fibroblast cells. We thank the iPSC CRISPR Facility from the University Medical Center Groningen and ERIBA for assistance with the generation of PHF6 knockout cell lines, David Egan from the Cell Screening Core at the Department of Cell Biology from the UMC Utrecht with technical assistance for screening, Govind Pai from Oncogenetics at the Amsterdam UMC for technical assistance with flow cytometry, the Bioimaging, Flow Cytometry facilities at the Netherlands Cancer Institute for their support, and Antonio Catal{\'a}n, Luciano Ben{\'i}tez, and Pilar Vaswani (Servicio de F{\'i}sica M{\'e}dica) from the Hospital Universitario de Canarias for use of the WOmed X-Ray Therapy Unit. We thank Louis Vermeulen for advice and critical reading of the manuscript. This work was supported by the Cancer Center Amsterdam (DOW, RMFW), Ministerio de Ciencia, Innovaci{\'o}n y Universidades (SAF2016-80626-R to RF and VAJS and BFU2017-90889-REDT to VAJS), co-funded by EU-ERDF. IAV is supported by a predoctoral fellowship from the Gobierno de Canarias and HvA by an ERC Consolidator grant from the European Research Council and a VICI grant from the Netherlands Organization for Scientific Research. Funding Information: We thank Jozef G{\'e}cz for sharing GFP‐PHF6, Susan Janicki for YFP‐BRD2, Thijn Brummelkamp for the pTIA‐Puro vector, Feng Zhang for pX458 (Addgene plasmid \#48138), and Bernard Lopes for the GC92 fibroblast cells. We thank the iPSC CRISPR Facility from the University Medical Center Groningen and ERIBA for assistance with the generation of PHF6 knockout cell lines, David Egan from the Cell Screening Core at the Department of Cell Biology from the UMC Utrecht with technical assistance for screening, Govind Pai from Oncogenetics at the Amsterdam UMC for technical assistance with flow cytometry, the Bioimaging, Flow Cytometry facilities at the Netherlands Cancer Institute for their support, and Antonio Catal{\'a}n, Luciano Ben{\'i}tez, and Pilar Vaswani (Servicio de F{\'i}sica M{\'e}dica) from the Hospital Universitario de Canarias for use of the WOmed X‐Ray Therapy Unit. We thank Louis Vermeulen for advice and critical reading of the manuscript. This work was supported by the Cancer Center Amsterdam (DOW, RMFW), Ministerio de Ciencia, Innovaci{\'o}n y Universidades (SAF2016‐80626‐R to RF and VAJS and BFU2017‐90889‐REDT to VAJS), co‐funded by EU‐ERDF. IAV is supported by a predoctoral fellowship from the Gobierno de Canarias and HvA by an ERC Consolidator grant from the European Research Council and a VICI grant from the Netherlands Organization for Scientific Research. Publisher Copyright: {\textcopyright} 2019 The Authors. Published under the terms of the CC BY 4.0 license",
year = "2020",
month = jan,
day = "7",
doi = "10.15252/embr.201948460",
language = "English",
volume = "21",
journal = "EMBO reports",
issn = "1469-221X",
publisher = "Wiley Blackwell",
number = "1",
}
SDG 3 Good Health and Well-being