PHD Finger Protein 2 (PHF2) Represses Ribosomal RNA Gene Transcription by Antagonizing PHF Finger Protein 8 (PHF8) and Recruiting Methyltransferase SUV39H1

Shi, Guang; Wu, Maomao; Lan, Fang; Yu, Fang; Cheng, Shimeng; Li, Jiwen; Du, James X.; Wong, Jiemin

doi:10.1074/jbc.m114.571653

Cited by 20 publications

(22 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Inhibition of the JmjC demethylase JHDM1A/KDM2A by dimethyl succinate induces pre-rRNA synthesis during starvation in breast cancer cells (83). Similarly, loss of the PHF2/KDM7B JmjC demethylase increases pre-rRNA synthesis in colon and lung cancer cells (185). Consistent with these findings, the expression of JHDM1B/KDM2B, a JmjC demethylase that is found in the nucleolus and that is required for rDNA silencing, is significantly downregulated in glioblastoma (84).…”

Section: Disease Progressionsupporting

confidence: 73%

The Epigenetic Pathways to Ribosomal DNA Silencing

Srivastava

Ahn

2016

Microbiol Mol Biol Rev

View full text Add to dashboard Cite

SUMMARYHeterochromatin is the transcriptionally repressed portion of eukaryotic chromatin that maintains a condensed appearance throughout the cell cycle. At sites of ribosomal DNA (rDNA) heterochromatin, epigenetic states contribute to gene silencing and genome stability, which are required for proper chromosome segregation and a normal life span. Here, we focus on recent advances in the epigenetic regulation of rDNA silencing inSaccharomyces cerevisiaeand in mammals, including regulation by several histone modifications and several protein components associated with the inner nuclear membrane within the nucleolus. Finally, we discuss the perturbations of rDNA epigenetic pathways in regulating cellular aging and in causing various types of diseases.

show abstract

Section: Disease Progressionsupporting

confidence: 73%

The Epigenetic Pathways to Ribosomal DNA Silencing

Srivastava

Ahn

2016

Microbiol Mol Biol Rev

View full text Add to dashboard Cite

show abstract

“…PHF2 was recently detected as genome-wide significant at the latest meta-analysis of depression 80 . Notably, PHF2 paralogs have already been link with MDD through stress-response in three other studies 91-93 . Joint effects in GS also detected an additional significant association upstream CYLC2 , a gene nominally associated (p < 1×10’ 5 ) with obsessive-compulsive disorder and Tourette’s Syndrome 94 .…”

Section: Discussionmentioning

confidence: 94%

Genome-wide by environment interaction studies (GWEIS) of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland

Soler

Macdonald-Dunlop

Adams

et al. 2018

Preprint

View full text Add to dashboard Cite

Stress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by environment interaction studies (GWEIS) of depressive symptoms and stressful life events (SLE) in two UK population cohorts (Generation Scotland and UK Biobank). No SNP was individually significant in either GWAS, but gene-based tests identified six genes associated with depressive symptoms in UK Biobank (DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU; p < 2.77×10-6). Two SNPs with genome-wide significant GxE effects were identified by GWEIS in Generation Scotland: rs12789145 (53kb downstream PIWIL4; p = 4.95×10-9; total SLE) and rs17070072 (intronic to ZCCHC2; p = 1.46×10-8; dependent SLE). A third locus upstream CYLC2 (rs12000047 and rs12005200, p < 2.00×10-8; dependent SLE) when the joint effect of the SNP main and GxE effects was considered. GWEIS gene-based tests identified: MTNR1B with GxE effect with dependent SLE in Generation Scotland; and PHF2 with the joint effect in UK Biobank (p < 2.77×10-6). Polygenic risk scores (PRS) analyses incorporating GxE effects improved the prediction of depressive symptom scores, when using weights derived from either the UK Biobank GWAS of depressive symptoms (p = 0.01) or the PGC GWAS of major depressive disorder (p = 5.91×10-3). Using an independent sample, PRS derived using GWEIS GxE effects provided evidence of shared aetiologies between depressive symptoms and schizotypal personality, heart disease and COPD. Further such studies are required and may result in improved treatments for depression and other stress-related conditions.

show abstract

“…Interestingly, NF-kB was shown to regulate HR by controlling BRCA1-CtIP complexes, although this effect is not mediated by transcriptional regulation of BRCA1 and CtIP (50). While we consider it likely that PHF2 demethylase activity is required for this function, we cannot rule out another mechanism for PHF2 action, as PHF2 was also demonstrated to repress transcription in a manner dependent on its methylated H3K4 binding activity yet independent on its demethylase activity (51). Instead, PHF2 was thought to repress transcription by competition with PHF8 for binding of the promoter and by recruiting SUV39H1, the H3K9me2/3 methyltransferase (51).…”

Section: Discussionmentioning

confidence: 85%

“…While we consider it likely that PHF2 demethylase activity is required for this function, we cannot rule out another mechanism for PHF2 action, as PHF2 was also demonstrated to repress transcription in a manner dependent on its methylated H3K4 binding activity yet independent on its demethylase activity (51). Instead, PHF2 was thought to repress transcription by competition with PHF8 for binding of the promoter and by recruiting SUV39H1, the H3K9me2/3 methyltransferase (51). In this respect, it is also important to mention that dimethylation of H4K20 is critical in the recruitment of 53BP1 to sites of DNA lesions (52,53).…”

Section: Discussionmentioning

confidence: 92%

PHF2 regulates homology-directed DNA repair by controlling the resection of DNA double strand breaks

Vega¹,

Paz-Cabrera²,

Wiegant³

et al. 2019

Preprint

View full text Add to dashboard Cite

Post-translational histone modifications and chromatin remodelling play a critical role in the mechanisms controlling the integrity of the genome. Here we identify histone lysine demethylase PHF2 as a novel regulator of the DNA damage response by regulating the balance between DNA damage-induced focus formation by 53BP1 and BRCA1, critical factors in the pathway choice for DNA double strand break repair. PHF2 knock down leads to impaired BRCA1 focus formation and delays the resolution of 53BP1 foci. Moreover, irradiation-induced RPA phosphorylation and focus formation, as well as localization of CtIP, required for DNA end resection, to sites of DNA lesions are affected by depletion of PHF2. These results are indicative of a defective resection of double strand breaks and thereby an impaired homologous recombination upon PHF2 depletion. In accordance with these data, Rad51 focus formation and homology-directed double strand break repair is inhibited in cells depleted for PHF2. Importantly, we demonstrate that PHF2 knock down decreases CtIP and BRCA1 protein and mRNA levels and cells depleted of PHF2 display genome instability and are sensitive to the inhibition of PARP. Together these results demonstrate that PHF2 promotes DNA repair by homologous recombination by controlling CtIP-dependent resection of double strand breaks.

show abstract

PHD Finger Protein 2 (PHF2) Represses Ribosomal RNA Gene Transcription by Antagonizing PHF Finger Protein 8 (PHF8) and Recruiting Methyltransferase SUV39H1

Cited by 20 publications

References 40 publications

The Epigenetic Pathways to Ribosomal DNA Silencing

The Epigenetic Pathways to Ribosomal DNA Silencing

Genome-wide by environment interaction studies (GWEIS) of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland

PHF2 regulates homology-directed DNA repair by controlling the resection of DNA double strand breaks

Contact Info

Product

Resources

About