Involvement of H4(D10S170) protein in ATM-dependent response to DNA damage

Merolla, Francesco; Pentimalli, Francesca; Pacelli, Roberto; Vecchio, Giancarlo; Fusco, Alfredo; Grieco, Michèle; Celetti, Angela

doi:10.1038/sj.onc.1210446

Cited by 46 publications

(63 citation statements)

References 37 publications

(33 reference statements)

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“…Moreover, CCDC6 inhibits CREB1 activity by activating HDAC1 that results in a decreased acetylation status of histone H3 at the CREB1 responsive promoters. All these results, showing that CCDC6 is able to reduce CREB1 activity, account for the inhibition of cell growth induced by CCDC6, as already shown (Merolla et al, 2007).…”

Section: Ccdc6 Represses Creb1 Activitysupporting

confidence: 81%

“…More recently, it has been shown that CCDC6 is involved in ATM-mediated cellular response to DNA damage, supporting the idea that the impairment of CCDC6 gene function might have a function in thyroid carcinogenesis (Merolla et al, 2007). The aim of our work has been to further characterize the function of the CCDC6 protein first by searching for the interacting proteins.…”

Section: Introductionmentioning

confidence: 58%

“…TPC1 cells are derived from PTC, which harbors the RET/PTC1 rearrangement and have lost the expression of the normal unrearranged CCDC6 allele. B-CPAP and TPC1 cells were maintained as reported elsewhere (Dettori et al, 2004;Merolla et al, 2007). B-CPAP cells were transfected by …”

Section: Methodsmentioning

confidence: 99%

“…The expression CCDC6 and mutant CCDC6 (1-101) plasmids and small-interfering RNAs (CCDC6i-345) have been described elsewhere (Celetti et al, 2004;Merolla et al, 2007). The expression plasmid pCMVSPORT6-CREB1 was from Invitrogen (Carlsbad, CA, USA).…”

Section: Expression Constructsmentioning

confidence: 99%

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CCDC6 represses CREB1 activity by recruiting histone deacetylase 1 and protein phosphatase 1

et al. 2010

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RET/papillary thyroid carcinoma 1 (PTC1) oncogene is frequently activated in human PTCs. It is characterized by the fusion of the intracellular kinase-encoding domain of RET to the first 101 amino acids of CCDC6. The aim of our work is to characterize the function of the CCDC6 protein to better understand the function of its truncation, that results in the loss of the expression of one allele, in the process of thyroid carcinogenesis. Here, we report that CCDC6 interacts with CREB1 and represses its transcriptional activity by recruiting histone deacetylase 1 and protein phosphatase 1 proteins at the CRE site of the CREB1 target genes. Finally, we show an increased CREB1 phosphorylation and activity in PTCs carrying the RET/PTC1 oncogene. Consistently, an increased expression of two known CREB1 target genes, AREG and cyclin A, was observed in this subgroup of thyroid papillary carcinomas. Therefore, the repression of CREB1 activity by CCDC6 has a critical function in the development of human thyroid papillary carcinomas carrying RET/PTC1 activation.

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Section: Ccdc6 Represses Creb1 Activitysupporting

confidence: 81%

Section: Introductionmentioning

confidence: 58%

Section: Methodsmentioning

confidence: 99%

Section: Expression Constructsmentioning

confidence: 99%

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CCDC6 represses CREB1 activity by recruiting histone deacetylase 1 and protein phosphatase 1

et al. 2010

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“…14,15 In previous work, we documented that CCDC6 (coiled-coildomain containing 6) acts as a proapoptotic protein substrate of ATM, to sustain DNA damage checkpoints in response to genotoxic events. 16,17 Moreover, CCDC6 protects genome integrity by modulating the activity of the phosphatase PP4C directed toward the dephosphorylation on S139 of the histone H2AX (gH2AX) in response to DNA damage. 18 Consistent with this, we reported that CCDC6 deficiency affects the gH2AX foci formation and the repair of the DNA DSBs.…”

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confidence: 99%

New therapeutic perspectives in CCDC6 deficient lung cancer cells

Morra

Luise

Visconti

et al. 2014

Intl Journal of Cancer

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Non-small cell lung cancer (NSCLC) is the main cause of cancer-related death worldwide and new therapeutic strategies are urgently needed. In this study, we have characterized a panel of NSC lung cancer cell lines for the expression of coiled-coildomain containing 6 (CCDC6), a tumor suppressor gene involved in apoptosis and DNA damage response. We show that low CCDC6 protein levels are associated with a weak response to DNA damage and a low number of Rad51 positive foci. Moreover, CCDC6 deficient lung cancer cells show defects in DNA repair via homologous recombination. In accordance with its role in the DNA damage response, CCDC6 attenuation confers resistance to cisplatinum, the current treatment of choice for NSCLC, but sensitizes the cells to olaparib, a small molecule inhibitor of the repair enzymes PARP1/2. Remarkably, the combination of the two drugs is more effective than each agent individually, as demonstrated by a combination index <1. Finally, CCDC6 is expressed at low levels in about 30% of the NSCL tumors we analyzed by TMA immunostaining. The weak CCDC6 protein staining is significatively correlated with the presence of lymph node metastasis (p 0.02) and negatively correlated to the disease free survival (p 0.01) and the overall survival (p 0.05). Collectively, the data indicate that CCDC6 levels provide valuable insight for OS. CCDC6 could represent a predictive biomarker of resistance to conventional single mode therapy and yield insight on tumor sensitivity to PARP inhibitors in NSCLC.

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CCDC6: the identity of a protein known to be partner in fusion

Cerrato

Merolla

Morra

et al. 2017

Intl Journal of Cancer

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Coiled Coil Domain Containing 6 gene, CCDC6, was initially isolated as part of a tumorigenic DNA originated by the fusion of CCDC6 with the tyrosine kinase of RET receptor, following a paracentric inversion of chromosome 10. For a long time, CCDC6 has been considered as an accidental partner of the RET protooncogene, providing the promoter and the first 101 aa necessary for the constitutive activation of the oncogenic Tyrosine Kinase (TK) RET in thyroid cells. With the advent of more refined diagnostic tools and bioinformatic algorithms, an exponential growth in fusion genes discoveries has allowed the identification of CCDC6 as partner of genes other than RET in different tumor types. CCDC6 gene product has a proper role in sustaining the DNA damage checkpoints in response to DNA damage. The inactivation of CCDC6 secondary to chromosomal rearrangements or gene mutations could enhance tumor progression by impairing the apoptotic response upon the DNA damage exposure, contributing to the generation of radio- and chemoresistance. Preclinical studies indicate that the attenuation of CCDC6 in cancer, while conferring a resistance to cisplatinum, sensitizes the cancer cells to the small molecule inhibitors of Poly (ADP-ribose) polymerase (PARP1/2) with a synthetic lethal effect. Several CCDC6 mutations and gene rearrangements have been described so far in different types of cancer and CCDC6 may represent a possible predictive biomarker of tumor resistance to the conventional anticancer treatments. Nevertheless, the detection of a CCDC6 impairment in cancer patients may help to select, in future clinical trials, those patients who could benefit of PARP-inhibitors treatment alone or in combination with other treatments.

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Involvement of H4(D10S170) protein in ATM-dependent response to DNA damage

Cited by 46 publications

References 37 publications

CCDC6 represses CREB1 activity by recruiting histone deacetylase 1 and protein phosphatase 1

CCDC6 represses CREB1 activity by recruiting histone deacetylase 1 and protein phosphatase 1

New therapeutic perspectives in CCDC6 deficient lung cancer cells

CCDC6: the identity of a protein known to be partner in fusion

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