Oncogenic Role of KIAA0101 Interacting with Proliferating Cell Nuclear Antigen in Pancreatic Cancer

Hosokawa, Munetaka; Takehara, Akio; Matsuda, Koichi; Eguchi, Hidetoshi; Ohigashi, Hajime; Ishikawa, Osamu; Shinomura, Yasuhisa; Imai, Kohzoh; Nakamura, Yusuke; Nakagawa, Hidewaki

doi:10.1158/0008-5472.can-06-4356

Cited by 81 publications

(137 citation statements)

References 24 publications

(42 reference statements)

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“…Tandem mass spectroscopy (MS/MS) identified copurifying proteins. Accordingly, we identified PCNA as having a strong interaction with PAF15, as has been reported by others (11)(12)(13)(14). Silver staining of the immunoprecipitates together with MS/MS data suggested that PAF15 is stoichiometrically associated with PCNA in a 1:1 complex (Fig.…”

Section: Paf15supporting

confidence: 85%

Proliferating cell nuclear antigen (PCNA)-associated KIAA0101/PAF15 protein is a cell cycle-regulated anaphase-promoting complex/cyclosome substrate

Emanuele

Ciccia

Elia

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

108

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The anaphase-promoting complex/cyclosome (APC/C) is a cell cycleregulated E3 ubiquitin ligase that controls the degradation of substrate proteins at mitotic exit and throughout the G1 phase. We have identified an APC/C substrate and cell cycle-regulated protein, KIAA0101/PAF15. PAF15 protein levels peak in the G2/M phase of the cell cycle and drop rapidly at mitotic exit in an APC/C-and KEN-box-dependent fashion. PAF15 associates with proliferating cell nuclear antigen (PCNA), and depletion of PAF15 decreases the number of cells in S phase, suggesting a role for it in cell cycle regulation. Following irradiation, PAF15 colocalized with γH2AX foci at sites of DNA damage through its interaction with PCNA. Finally, PAF15 depletion led to an increase in homologous recombinationmediated DNA repair, and overexpression caused sensitivity to UV-induced DNA damage. We conclude that PAF15 is an APC/Cregulated protein involved in both cell cycle progression and the DNA damage response.DNA replication | proteolysis

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Section: Paf15supporting

confidence: 85%

Proliferating cell nuclear antigen (PCNA)-associated KIAA0101/PAF15 protein is a cell cycle-regulated anaphase-promoting complex/cyclosome substrate

Emanuele

Ciccia

Elia

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

108

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“…We further show that p15 PAF constitutes a major effector of ATF3 for DNA repair. Although p15 PAF downregulation seems to be dependent on the p53-p21 pathway, 18 we show here, that after UV treatment, ATF3 is directly responsible for p15 PAF expression. p15 PAF also known as PCNA-associated factor, KIAA0101 or OEATC-1, 16,17 has been shown to localize to the mitochondria and the nucleus.…”

Section: Discussioncontrasting

confidence: 48%

“…It is therefore tempting to speculate that the lack of ATF3 expression contributes to the impaired DNA damage response responsible for oncogenesis. Although upregulation and oncogenic function of p15 PAF has been described in esophageal tumors 17 and in pancreatic cancer, 18 a putative tumor suppressor function has been suggested by its downregulation in several human colorectal tumors and hepatocellular carcinoma. 16,27 As the downregulation does not appear to be related to mutations, 16 it is possible that reduction in the levels of p15 PAF is mediated by the lack of ATF3 expression.…”

Section: Discussionmentioning

confidence: 99%

ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress

et al. 2009

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After genotoxic stress, normal cells trigger DNA repair or, if unable to repair, undergo apoptosis to eradicate the cells that bear the risk of becoming tumorigenic. Here we show that repression of the transcription factor, activating transcription factor 3 (ATF3), after ultraviolet (UV)-mediated genotoxic stress impairs the DNA repair process. We provide evidence that ATF3 directly regulates the proliferating cell nuclear antigen (PCNA)-associated factor KIAA0101/p15 PAF . We further show that the expressions of ATF3 and p15 PAF is sufficient to trigger the DNA repair machinery, and that attenuation of their expression alters DNA repair mechanisms. We show that the expression of p15 PAF compensates for a lack of ATF3 expression, thereby constituting a major effector of ATF3 in the DNA repair process. In addition, we provide evidence that p15 PAF expression is required for the correct function of PCNA during DNA repair, as prevention of their interaction significantly alters DNA repair mechanisms. Finally, defective DNA repair, because of the downregulation of p15 PAF expression, rendered the cells more sensitive to UV-induced cell death. Therefore, our results suggest ATF3 and p15 PAF as novel gatekeepers of genomic integrity after UV exposure. Environmental genotoxic stress is one of the major causes of genomic instability. During such a stress, the maintenance of genomic integrity is of crucial importance to allow correct cellular function. The nucleotide excision repair (NER) machinery is responsible for recognition and incision of DNA lesions caused by ultraviolet (UV) irradiation and chemical agents. 1 Proliferating cell nuclear antigen (PCNA) is responsible for recruitment of Pold and, therefore, mediates DNA resynthesis within the site of the lesion. 1 The importance of such machinery is underscored by the numerous human syndromes, such as xeroderma pigmentosum (XP) and trichothiodystrophy (TTD), caused by the mutation of genes involved in DNA repair. Such mutations compromise genomic integrity, and XP and TTD patients are highly photosensitive and prone to develop skin tumors of keratinocyte origin, such as basal and squamous cell carcinoma. Severe defects in the DNA repair mechanism thus impair the apoptotic pathway responsible for destruction of cells that bear the risk of becoming tumorigenic. The correct DNA damage response is therefore of great importance in the maintenance of a UV-inducible anticancer barrier that elicits growth arrest, repair or cell death.Activating transcription factor 3 (ATF3) is a member of the ATF/CREB subfamily of the basic region leucine zipper (bZIP) family and may be strongly induced in a variety of tissues by different stress signals. 2 Several pathways are responsible for ATF3 induction, such as ATM and Nibrin 1, JNK and NF-kB, in a p53-dependent or -independent manner. 3-5 Induction of ATF3 often correlates with cellular damage, suggesting an important role during the cellular stress response. 6 We have recently reported that the alteration of Egr-1 expression during ...

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“…Overexpression of p15 correlates with tumour progression and poor prognosis in a number of human cancers [13][14][15][16] . Evidence for p15-PCNA interaction comes from yeast two-hybrid and co-immunoprecipitation experiments, but no structural detail of the direct interaction is known.…”

mentioning

confidence: 99%

Structure of p15PAF–PCNA complex and implications for clamp sliding during DNA replication and repair

et al. 2015

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The intrinsically disordered protein p15 PAF regulates DNA replication and repair by binding to the proliferating cell nuclear antigen (PCNA) sliding clamp. We present the structure of the human p15 PAF -PCNA complex. Crystallography and NMR show the central PCNA-interacting protein motif (PIP-box) of p15 PAF tightly bound to the front-face of PCNA. In contrast to other PCNA-interacting proteins, p15 PAF also contacts the inside of, and passes through, the PCNA ring. The disordered p15 PAF termini emerge at opposite faces of the ring, but remain protected from 20S proteasomal degradation. Both free and PCNA-bound p15 PAF binds DNA mainly through its histone-like N-terminal tail, while PCNA does not, and a model of the ternary complex with DNA inside the PCNA ring is consistent with electron micrographs. We propose that p15 PAF acts as a flexible drag that regulates PCNA sliding along the DNA and facilitates the switch from replicative to translesion synthesis polymerase binding.

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Oncogenic Role of KIAA0101 Interacting with Proliferating Cell Nuclear Antigen in Pancreatic Cancer

Cited by 81 publications

References 24 publications

Proliferating cell nuclear antigen (PCNA)-associated KIAA0101/PAF15 protein is a cell cycle-regulated anaphase-promoting complex/cyclosome substrate

Proliferating cell nuclear antigen (PCNA)-associated KIAA0101/PAF15 protein is a cell cycle-regulated anaphase-promoting complex/cyclosome substrate

ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress

Structure of p15PAF–PCNA complex and implications for clamp sliding during DNA replication and repair

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