SPOC1: a novel PHD-containing protein modulating chromatin structure and mitotic chromosome condensation

Kinkley, Sarah; Staege, Hannah; Mohrmann, Gerrit; Rohaly, Gabor; Schaub, Thomas; Kremmer, Elisabeth; Winterpacht, Andreas; Will, Hans

doi:10.1242/jcs.047365

Cited by 29 publications

(77 citation statements)

References 57 publications

(70 reference statements)

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“…SPOC1 is proposed to increase histone H3 lysine 9 (H3K9) lysine methyltransferases (KMTs) and trimethylated H3K9 (H3K9me3) histone marks to promote chromatin condensation by recruiting histone methyltransferases (HMTs). We found that SPOC1 protein levels were decreased in HAdV-infected cells, which we could attribute to proteasomal degradation mediated by the E1B-55K/E4orf6 E3 ligase complex (8).…”

mentioning

confidence: 78%

“…Primary antibodies specific for the viral proteins used in this study included E1A mouse monoclonal antibody (MAb) M73 (35), E1B-55K mouse MAb 2A6 (36), E2A-72K mouse MAb B6-8 (37), E4orf6 mouse MAb RSA3 (38), L4-100K rat MAb 6B-10 (39), E4orf3 rat MAb 6A11 (40), and HAdV type 5 (HAdV5) rabbit polyclonal serum L133 (34). Primary antibodies specific for cellular proteins included KAP1 rabbit polyclonal antibody H-300 (Santa Cruz Biotechnology), phospho-KAP1 (S824) rabbit polyclonal antibody (Bethyl Laboratories, Inc.), SPOC1 rat monoclonal antibody 6F6 (8,10), GAPDH 2542 KAP1S824A fwd 5=-CTGGCCTGAGTGCCCAGGAGCTG-3= 2543 KAP1S824A rev 5=-CAGCTCCTGGGCACTCAGGCCAG-3= 2548 KAP1K554A fwd 5=-GTCTCCTCCTCCGCGACAATGG-3= 2549 KAP1K554A rev 5=-CCATTGTCGCGGAGGAGGAGAC-3= 2550 KAP1K779A fwd 5=-TGCACGTCTGCCGCGTCCTCAG-3= 2551 KAP1K779A rev 5=-CTGAGGACGCGGCAGACGTGCA-3= 2552 KAP1K804A fwd 5=-ACAGCAGAGAACGCGGTGTCACC-3= 2553 KAP1K804A rev 5=-GGTGACACCGCGTTCTCTGCTGT-3= 2645 KAP1K676A fwd 5=-CATCCTCCTCCGCCAGGTCAGG-3= 2646 KAP1K676A rev 5=-CCTGACCTGGCGGAGGAGGATG-3=…”

Section: Methodsmentioning

confidence: 99%

“…We have also shown that HAdV inhibits the SPOC1 restriction factor, which is dynamically associated with chromatin and induces chromosome condensation to regulate proper cell division (8). SPOC1 is proposed to increase histone H3 lysine 9 (H3K9) lysine methyltransferases (KMTs) and trimethylated H3K9 (H3K9me3) histone marks to promote chromatin condensation by recruiting histone methyltransferases (HMTs).…”

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confidence: 99%

“…Recruitment of this protein to genetic loci increases H3K9me2/3 repressive histone marks, induces the formation of heterochromatin, and blocks gene expression (8). Upon DNA damage, KAP1 is rapidly phosphorylated at serine 824 (S824) by the nuclear phosphatidylinositol 3 kinase-like (PIKK) family members ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3 related (ATR), and the DNA-dependent protein kinase catalytic subunit (DNAPKcs).…”

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confidence: 99%

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KAP1 Is a Host Restriction Factor That Promotes Human Adenovirus E1B-55K SUMO Modification

Bürck

Mund

Berscheminski

et al. 2016

J Virol

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Once transported to the replication sites, human adenoviruses (HAdVs) need to ensure decondensation and transcriptional activation of their viral genomes to synthesize viral proteins and initiate steps to reprogram the host cell for viral replication. These early stages during adenoviral infection are poorly characterized but represent a decisive moment in the establishment of a productive infection. Here, we identify a novel host viral restriction factor, KAP1. This heterochromatin-associated transcription factor regulates the dynamic organization of the host chromatin structure via its ability to influence epigenetic marks and chromatin compaction. In response to DNA damage, KAP1 is phosphorylated and functionally inactive, resulting in chromatin relaxation. We discovered that KAP1 posttranslational modification is dramatically altered during HAdV infection to limit the antiviral capacity of this host restriction factor, which represents an essential step required for efficient viral replication. Conversely, we also observed during infection an HAdV-mediated decrease of KAP1 SUMO moieties, known to promote chromatin decondensation events. Based on our findings, we provide evidence that HAdV induces KAP1 deSUMOylation to minimize epigenetic gene silencing and to promote SUMO modification of E1B-55K by a so far unknown mechanism. IMPORTANCEHere we describe a novel cellular restriction factor for human adenovirus (HAdV) that sheds light on very early modulation processes in viral infection. We reported that chromatin formation and cellular SWI/SNF chromatin remodeling play key roles in HAdV transcriptional regulation. We observed that the cellular chromatin-associated factor and epigenetic reader SPOC1 represses HAdV infection and gene expression. Here, we illustrate the role of the SPOC1-interacting factor KAP1 during productive HAdV growth. KAP1 binds to the viral E1B-55K protein, promoting its SUMO modification, therefore illustrating a crucial step for efficient viral replication. Simultaneously, KAP1 posttranslational modification is dramatically altered during infection. We observed an HAdV-mediated decrease in KAP1 SUMOylation, known to promote chromatin decondensation events. These findings indicate that HAdV induces the loss of KAP1 SUMOylation to minimize epigenetic gene silencing and to promote the SUMO modification of E1B-55K by a so far unknown mechanism.

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mentioning

confidence: 78%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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KAP1 Is a Host Restriction Factor That Promotes Human Adenovirus E1B-55K SUMO Modification

Bürck

Mund

Berscheminski

et al. 2016

J Virol

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“…4 Therefore, the phosphorylation status of the CTD domain and key regulatory interacting factors is mediated by specific Cdk kinases, which in turn regulates the transcription cycle. Interestingly, PHF13 also contains several putative SP/TP Cdk phosphorylation sites and a Cdk consensus sequence S/T RX K/ R, 13 raising the possibility that it may also be a substrate of Cdk7 and/or Cdk9.…”

Section: Rnapii Ctd Modification and The Transcription Cyclementioning

confidence: 99%

PHF13: A new player involved in RNA polymerase II transcriptional regulation and co-transcriptional splicing

2017

Self Cite

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We recently identified PHF13 as an H3K4me2/3 chromatin reader and transcriptional co-regulator. We found that PHF13 interacts with RNAPIIS5P and PRC2 stabilizing their association with active and bivalent promoters. Furthermore, mass spectrometry analysis identified »50 spliceosomal proteins in PHF13s interactome. Here, we will discuss the potential role of PHF13 in RNAPII pausing and co-transcriptional splicing.

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Fibroblast growth factor receptor 3 is highly expressed in rarely dividing human type A spermatogonia

Kopylow

Staege

Schulze

et al. 2012

Histochem Cell Biol

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Human spermatogonia (Spg) and their fetal precursors express fibroblast growth factor receptor 3 (FGFR3). To further elucidate the role of FGFR3 in the control of Spg self-renewal, proliferation, and/or differentiation, and to narrow down the FGFR3-positive cell type(s) in the normal adult human testis, tissue sections and whole mount preparations of seminiferous tubules were analyzed combining immunofluorescence and confocal fluorescence microscopy. FGFR3 protein was chiefly observed in cellular membranes and cytoplasmic vesicles of a subpopulation of type A Spg, which comprised the chromatin rarefaction zone-containing type A(dark). Cytoplasmic expression of FGFR3 and nuclear expression of proliferation-associated antigen KI-67 were mutually exclusive. Similarly, FGFR3-positive Spg were negative for Doublesex and Mab-3 related transcription factor 1 (DMRT1). By contrast, undifferentiated embryonic cell transcription factor 1 (UTF1) and survival time-associated PHD finger in ovarian cancer 1 protein (SPOC1) were co-expressed in the nuclei of FGFR3-positive Spg. Whole mounted seminiferous tubules illustrated the clonogenic arrangement of the FGFR3/UTF1 double-positive Spg, which mainly occurred as pairs or quadruplets and, different from the KIT-positive Spg, showed no overlap with KI-67 labeled clusters. Taken together, in the adult human testis, FGFR3 expression is a feature of small clones of rarely dividing type A Spg which resemble "undifferentiated" Spg, including the spermatogonial stem cells.

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SPOC1: a novel PHD-containing protein modulating chromatin structure and mitotic chromosome condensation

Cited by 29 publications

References 57 publications

KAP1 Is a Host Restriction Factor That Promotes Human Adenovirus E1B-55K SUMO Modification

KAP1 Is a Host Restriction Factor That Promotes Human Adenovirus E1B-55K SUMO Modification

PHF13: A new player involved in RNA polymerase II transcriptional regulation and co-transcriptional splicing

Fibroblast growth factor receptor 3 is highly expressed in rarely dividing human type A spermatogonia

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