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PHF6 regulates cell cycle progression by suppressing ribosomal RNA synthesis

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Mutation of PHF6, which results in X-linked mental retardation disorder-Börjeson-Forssman-Lehmann syndrome, is also present in about 38% of adult T-cell acute lymphoblastic leukemias and 3% of adult acute myeloid leukemias. However, it remains to be determined exactly how PHF6 acts in vivo and what functions of PHF6 may be associated with its putative tumor suppressor function. Here, we demonstrate that PHF6 is a nucleolus, ribosomal RNA promoter-associated protein. PHF6 directly interacts with UBF through its PHD1 domain and suppresses rRNA transcription by affecting the protein level of UBF. Knockdown of PHF6 impairs cell proliferation and arrests cells at G2/M phase, which is accompanied by increased level of phosphorylated H2AX (γ-H2AX), indicating that PHF6 deficiency leads to the accumulation of DNA damage in the cell. We found that increased DNA damage occurs at rDNA locus in PHF6-deficient cells. This effect could be reversed by knocking-down UBF or over-expressing RNASE1, which removes RNA:DNA hybrids, suggesting that there is a functional link between rRNA synthesis and genomic stability at rDNA locus. Together, these results reveal that the key function of PHF6 is involved in regulating rRNA synthesis, which may contribute to its roles in cell cycle control, genomic maintenance and tumor suppression.

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Correspondence to Jiadong Wang.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Keywords

  • Acute Myeloid Leukemia
  • Acute Lymphoblastic Leukemia
  • Lymphoblastic Leukemia
  • rDNA Locus
  • Tumor Suppressor Function