Functional characterization of the atopy-associated gene PHF11

Clarke, Emily; Rahman, Nusrat; Page, Natalie S.; Rolph, Michael S.; Stewart, Graeme J.; Jones, Graham

doi:10.1016/j.jaci.2008.02.028

Cited by 33 publications

(70 citation statements)

References 30 publications

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“…28 In light of the prognostic impact of P53 deregulation, this is an interesting avenue for further study. The deletion of other genes, such as PHF11, which is expressed in B-and T cells, and controls gene expression through interactions with the p65 subunit of NF-kB, 29 and RCBTB1, which has been implicated in ubiquitination through its role as a substrate for a CUL3 E3 ligase, 30 may also be important genes within the region. Interestingly, the result of a unique 13q deletion may be the loss of multiple genes that contribute to the disruption of a small number of key biological pathways, causing a variable degree of pathway dysfunction and a heterogeneous impact on prognosis.…”

Section: Discussionmentioning

confidence: 99%

13q deletion anatomy and disease progression in patients with chronic lymphocytic leukemia

et al. 2010

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Historically, genes targeted by recurrent chromosomal deletions have been identified within the smallest genomic region shared in all patients, the minimally deleted region (MDR). However, deletions this small do not occur in all patients and are a simplification of the impact larger heterogeneous deletions have during carcinogenesis. We use the example of 13q14 deletions in chronic lymphocytic leukemia to show that genes outside MDRs are associated with disease progression. Genomic profiling of 224 patients identified 205 copy number alterations on chromosome 13 in 132 cases. Deletions including DLEU2 were heterogeneous (845 Kb-96.2 Mb) and identified two breakpoint cluster regions within short interspersed nuclear elements proximal to DLEU2 and within long interspersed nuclear elements/L1 repeats distal to GUCY1B2. After defining a deletion class on the basis of size and location, we show that (a) at diagnosis, larger deletions (class II) were associated with a significantly increased risk of disease progression (odds ratio ¼ 12.3; P ¼ 0.005), (b) in progressive patients, class II deletions were enriched (P ¼ 0.02) and (c) this association was independent of IgVH mutational status, ZAP70 expression and ATM/TP53 deletion. Deletion of a 1 Mb gene cluster (48.2-49.2 Mb), including SETDB2, PHF11 and RCBTB1, was significantly associated (Po0.01) with disease progression. Here, we show that the deletion of genes outside MDRs can influence clinical outcome.

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Section: Discussionmentioning

confidence: 99%

13q deletion anatomy and disease progression in patients with chronic lymphocytic leukemia

et al. 2010

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“…A recent study has shown that PHF11 regulates the expression of Th1-type cytokine genes, and reduced expression of PHF11 in atopic dermatitis (a disease that commonly presents concomitant with asthma) causes strong Th2 responses characterizing asthma and allergic diseases [9]. In PHF11 , markers rs3765526 and rs1046295 have been associated with asthma in the general Australian population and are significantly linked to severe asthma in unrelated British individuals [4].…”

Section: Discussionmentioning

confidence: 99%

“…Marker rs1046295 is located in the 3′-UTR of PHF11 and has also been associated with childhood atopic dermatitis [17]. The G allele of rs1046295 is preferentially transmitted to children with atopic dermatitis and has been associated with decreased PHF11 RNA in Th1 cells [9]. Marker rs16659 is 4 kb away from rs1046295, positioned within the 5′-UTR of RCBTB1, and shows strong LD with rs1046295 (r 2 = 0.9, data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…The functions of the two genes are not fully understood. PHF11 on chromosome 13q14 is suggested to genetically impact asthma via serum total IgE regulation and altered Th1/Th2 cytokine release [4,9]; DPP10 , which is located on chromosome 2q14, is strongly associated with asthma susceptibility, possibly through regulating the activities of chemokines and cytokines [5]. …”

Section: Introductionmentioning

confidence: 99%

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Polymorphisms of <i>PHF11</i> and <i>DPP10 </i> Are Associated with Asthma and Related Traits in a Chinese Population

Gao

Willis‐Owen

et al. 2009

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Background: Initial studies by positional cloning have identified the genes encoding the plant homeodomain zinc finger protein 11 (PHF11) and dipeptidyl-peptidase 10 (DPP10) as asthma susceptibility genes. The variants in the two genes have been associated with asthma in several populations of European or Latin American origin. Objective: The aim of this study was to assess the common PHF11 and DPP10 polymorphisms for associations to asthma and asthma-related traits in a Han Chinese population. Methods: We genotyped six polymorphic markers in PHF11 and five polymorphic markers in DPP10 in a Han Chinese case-control cohort consisting of 408 asthma patients and 288 unrelated disease-free controls recruited from the Northern region of China. We analyzed the association between these markers and asthma as well as a number of intermediate, asthma-related traits. Linkage disequilibrium and haplotype patterns were also evaluated. Results: Significant associations were identified between two makers in PHF11 (rs1046295 and rs16659) and asthma susceptibility (odds ratio, OR = 1.32, 95% con fidence interval, CI = 1.06–1.65, p = 0.0096, for rs1046295, and OR = 1.41, 95% CI = 1.12–1.75, p = 0.0026, for rs16659). A strong association was observed between an SNP in DPP10 (rs10208402) and log_e-transformed total IgE (p = 0.0003) and the percentage of peripheral blood eosinophils (p = 0.0023). A weak association between rs1430090 in DPP10 and forced expiratory volume in 1 s was also observed (p = 0.048). Haplotype analysis revealed two protective haplotypes in PHF11 against asthma. Conclusion: The results provide supporting evidence for genetic variants in PHF11 and DPP10 genes underlying asthma susceptibility and asthma-related quantitative traits in a Han Chinese population.

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“…PHF11 is frequently methylated in Ewing's sarcoma (Alholle et al 2013), codeleted with a cluster of genes in CLL (Parker et al 2011), and deleted in 10%-20% of prostate cancers (cBioPortal for Cancer Genomics, http://www.cbioportal .org). PHF11 is most abundant in lymphocytes and is thought to act as a transcription factor that promotes class switching in the IgE locus in B cells (Clarke et al 2008;Ikari et al 2014). Polymorphisms in PHF11 are associated with atopic dermatitis (Zhang et al 2003).…”

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PHF11 promotes DSB resection, ATR signaling, and HR

et al. 2017

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Resection of double-strand breaks (DSBs) plays a critical role in their detection and appropriate repair. The 3 ′ ssDNA protrusion formed through resection activates the ATR-dependent DNA damage response (DDR) and is required for DSB repair by homologous recombination (HR). Here we report that PHF11 (plant homeodomain finger 11) encodes a previously unknown DDR factor involved in 5 ′ end resection, ATR signaling, and HR. PHF11 was identified based on its association with deprotected telomeres and localized to sites of DNA damage in S phase. Depletion of PHF11 diminished the ATR signaling response to telomere dysfunction and genome-wide DNA damage, reduced end resection at sites of DNA damage, resulted in compromised HR and misrejoining of S-phase DSBs, and increased the sensitivity to DNA-damaging agents. PHF11 interacted with the ssDNA-binding protein RPA and was found in a complex with several nucleases, including the 5 ′ dsDNA exonuclease EXO1. Biochemical experiments demonstrated that PHF11 stimulates EXO1 by overcoming its inhibition by RPA, suggesting that PHF11 acts (in part) by promoting 5 ′ end resection at RPA-bound sites of DNA damage. These findings reveal a role for PHF11 in DSB resection, DNA damage signaling, and DSB repair.[Keywords: PHF11; EXO1; RPA; ATR; DSB; resection; homologous recombination] Supplemental material is available for this article.Received October 9, 2016; revised version accepted December 22, 2016.Nuclear double-strand breaks (DSBs) activate the ATM and ATR kinase-dependent DNA damage response (DDR) pathways (for review, see Ciccia and Elledge 2010). Whereas the ATM kinase responds to the presence of dsDNA ends, activation of the ATR kinase requires the presence of ssDNA that is bound by RPA. In addition, activation of the ATR kinase requires the loading of the 9-1-1 complex on the double-stranded-single-stranded junction formed after 5 ′ end resection. Resection of the 5 ′ end of DSBs is therefore a critical step in the activation of ATR signaling. DSB resection is also required for the initiation of several DNA repair pathways, including homologous recombination (HR) and single-strand annealing (SSA) (for review, see Symington and Gautier 2011). HR can restore the original DNA sequence using the sister chromatid as a template for repair. After 5 ′ end resection, HR is initiated by the BRCA2-mediated loading of the Rad51 recombinase onto the ssDNA. In the absence of HR, S-phase DSBs can become a substrate for more error-prone DSB repair, including SSA and classical or alternative nonhomologous end-joining (NHEJ). DSB resection is initiated through the agency of BRCA1, the MRE11/RAD50/NBS1 (MRN) complex, and CtIP (for review, see Cejka 2015). The outcome is a ssDNA end with a short (∼20-nucleotide [nt]) 3 ′ overhang that is a substrate for further nucleolytic attack by EXO1, a dsDNA exonuclease that degrades only the 5 ′ strand to leave a 3 ′ overhang that can be thousands of nucleotides in length. In addition, an overlapping pathway involving the DNA2 nuclease acting in conjun...

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Functional characterization of the atopy-associated gene PHF11

Cited by 33 publications

References 30 publications

13q deletion anatomy and disease progression in patients with chronic lymphocytic leukemia

13q deletion anatomy and disease progression in patients with chronic lymphocytic leukemia

Polymorphisms of <i>PHF11</i> and <i>DPP10 </i> Are Associated with Asthma and Related Traits in a Chinese Population

PHF11 promotes DSB resection, ATR signaling, and HR

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