Pan Zhang

Rutgers New Jersey Medical School, Newark, New Jersey, United States

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Publications (9)64.33 Total impact

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    ABSTRACT: Nonerythroid α spectrin (αIISp) and the Fanconi anemia (FA) protein, FANCD2, play critical roles in DNA interstrand cross-link (ICL) repair during S phase. Both are needed for recruitment of repair proteins, such as XPF, to sites of damage and repair of ICLs. However, the relationship between them in ICL repair and whether αIISp is involved in FANCD2's function in repair is unclear. The present studies show that, after ICL formation, FANCD2 disassociates from αIISp and localizes, before αIISp, at sites of damage in nuclear foci. αIISp and FANCD2 foci do not co-localize, in contrast to our previous finding that αIISp and the ICL repair protein, XPF, co-localize and follow a similar time course for formation. Knock-down of αIISp has no effect on monoubiquitination of FANCD2 (FANCD2-Ub) or its localization to chromatin or foci, though it leads to decreased ICL repair. Studies using cells from FA patients, defective in ICL repair and αIISp, have elucidated an important role for αIISp in the function of non-Ub FANCD2. In FA complementation group A (FA-A) cells, in which FANCD2 is not monoubiquitinated and does not form damage-induced foci, we demonstrate that restoration of αIISp levels to normal, by knocking down the protease µ-calpain, leads to formation of non-Ub FANCD2 foci after ICL damage. Since restoration of αIISp levels in FA-A cells restores DNA repair and cell survival, we propose that αIISp is critical for recruitment of non-Ub FANCD2 to sites of damage, which has an important role in the repair response and ICL repair. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Cellular Biochemistry 08/2015; DOI:10.1002/jcb.25352 · 3.26 Impact Factor
  • Cancer Research 08/2015; 75(15 Supplement):3018-3018. DOI:10.1158/1538-7445.AM2015-3018 · 9.33 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):2380-2380. DOI:10.1158/1538-7445.AM2014-2380 · 9.33 Impact Factor
  • Pan Zhang · Muriel W. Lambert
    Cancer Research 08/2013; 73(8 Supplement):621-621. DOI:10.1158/1538-7445.AM2013-621 · 9.33 Impact Factor
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    ABSTRACT: Telomere integrity is critical for telomere function and genomic stability. We previously demonstrated that non-erythroid α-spectrin (αIISp) is present in mammalian cell nuclei where it is important in repair of DNA interstrand cross-links (ICLs) and chromosome stability. We now demonstrate that αIISp is also important for telomere maintenance after ICL damage. It localizes to telomeres in S phase after ICL damage where it has enhanced association with TRF1 and TRF2 and is required for recruitment of the ICL repair protein, XPF, to damage-induced foci at telomeres. In telomerase-positive normal cells depleted of αIISp by siRNA or in Fanconi anemia, complementation group A (FA-A) cells, where αIISp levels are 35-40% of normal, ICL damage results in failure of XPF to localize to telomeres, markedly increased telomere dysfunction-induced foci, followed by catastrophic loss of telomeres. Restoration of αIISp levels to normal in FA-A cells corrects these deficiencies. Our studies demonstrate that αIISp is critical for repair of DNA ICLs at telomeres, likely by facilitating the recruitment of repair proteins similar, but not identical, to its proposed role in repair of DNA ICLs in genomic DNA and that this function in turn is critical for telomere maintenance after DNA ICL damage.
    Nucleic Acids Research 04/2013; 41(10). DOI:10.1093/nar/gkt235 · 9.11 Impact Factor
  • Pan Zhang · Utz Herbig · Muriel W. Lambert
    Cancer Research 04/2012; 72(8 Supplement):2121-2121. DOI:10.1158/1538-7445.AM2012-2121 · 9.33 Impact Factor
  • Cancer Research 07/2011; 71(8 Supplement):3924-3924. DOI:10.1158/1538-7445.AM2011-3924 · 9.33 Impact Factor
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    ABSTRACT: We have previously shown that there is a deficiency in the structural protein, nonerythroid alpha spectrin (alphaIISp), in cells from patients with Fanconi anemia (FA). These studies indicate that this deficiency is due to the reduced stability of alphaIISp and correlates with a decreased level of repair of DNA interstrand cross-links and chromosomal instability in FA cells. An important factor in the stability of alphaIISp is its susceptibility to cleavage by the protease, mu-calpain. We hypothesized that an increased level of mu-calpain cleavage of alphaIISp in FA cells leads to an increased level of breakdown of alphaIISp and that knocking down expression of mu-calpain in FA cells should restore levels of alphaIISp and correct a number of the phenotypic defects observed. The results showed that there is increased mu-calpain activity in FA-A, FA-C, FA-D2, FA-F, and FA-G cells that could account for the deficiency in alphaIISp in these FA cells. Protein interaction studies indicated that FANCA and FANCG bind directly to mu-calpain. We hypothesize that this binding may lead to inhibition of mu-calpain activity in normal cells. Knocking down mu-calpain by siRNA in FA-A cells restored levels of alphaIISp to normal and reversed a number of the cellular deficiencies in these cells. It corrected the DNA repair defect and the chromosomal instability observed after exposure to a DNA interstrand cross-linking agent. These studies indicate that FA proteins may play an important role in maintaining the stability of alphaIISp in the cell by regulating its cleavage by mu-calpain. Thus, by reducing the level of breakdown of alphaIISp in FA cells, we may be able to reverse a number of the cellular deficiencies observed in this disorder.
    Biochemistry 07/2010; 49(26):5570-81. DOI:10.1021/bi100656j · 3.02 Impact Factor
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    ABSTRACT: Nonerythroid alpha-spectrin (alphaIISp) is a structural protein involved in repair of DNA interstrand cross-links and is deficient in cells from patients with Fanconi anemia (FA), which are defective in ability to repair cross-links. In order to further demonstrate the importance of the role that alphaIISp plays in normal human cells and in the repair defect in FA, alphaIISp was knocked down in normal cells using siRNA. Depletion of alphaIISp in normal cells by siRNA resulted in chromosomal instability and cellular hypersensitivity to DNA interstrand cross-linking agents. An increased number of chromosomal aberrations were observed and, following treatment with a DNA interstrand cross-linking agent, mitomycin C, cells showed decreased cell growth and survival and decreased formation of damage-induced alphaIISp and XPF nuclear foci. Thus depletion of alphaIISp in normal cells leads to a number of defects observed in FA cells, such as chromosome instability and a deficiency in cross-link repair.
    Biochemical and Biophysical Research Communications 03/2009; 381(2):288-93. DOI:10.1016/j.bbrc.2009.02.038 · 2.30 Impact Factor