De novo phosphorylation of H2AX by WSTF regulates transcription-coupled homologous recombination repair.
Histone H2AX undergoes a phosphorylation switch from pTyr142 (H2AX-pY142) to pSer139 (?H2AX) in the DNA damage response (DDR); however, the functional role of H2AX-pY142 remains elusive. Here, we report a new layer of regulation involving transcription-coupled H2AX-pY142 in the DDR. We found that constitutive H2AX-pY142 generated by Williams-Beuren syndrome transcription ... factor (WSTF) interacts with RNA polymerase II (RNAPII) and is associated with RNAPII-mediated active transcription in proliferating cells. Also, removal of pre-existing H2AX-pY142 by ATM-dependent EYA1/3 phosphatases disrupts this association and requires for transcriptional silencing at transcribed active damage sites. The following recovery of H2AX-pY142 via translocation of WSTF to DNA lesions facilitates transcription-coupled homologous recombination (TC-HR) in the G1 phase, whereby RAD51 loading, but not RPA32, utilizes RNAPII-dependent active RNA transcripts as donor templates. We propose that the WSTF-H2AX-RNAPII axis regulates transcription and TC-HR repair to maintain genome integrity.
Mesh Terms:
Cell Line, Tumor, DNA-Binding Proteins, G1 Phase, HEK293 Cells, HeLa Cells, Histones, Humans, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, Phosphorylation, Protein Tyrosine Phosphatases, RNA Polymerase II, Recombinational DNA Repair, Transcription Factors, Transcription, Genetic, Tyrosine
Cell Line, Tumor, DNA-Binding Proteins, G1 Phase, HEK293 Cells, HeLa Cells, Histones, Humans, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, Phosphorylation, Protein Tyrosine Phosphatases, RNA Polymerase II, Recombinational DNA Repair, Transcription Factors, Transcription, Genetic, Tyrosine
Nucleic Acids Res.
Date: Dec. 09, 2018
PubMed ID: 31045206
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