CCDC6 is a stress response protein that preserves genome stability upon interaction with the catalytic subunit of serine/threonine protein phosphatase 4 (PP4c)
Luise, Chiara (2011) CCDC6 is a stress response protein that preserves genome stability upon interaction with the catalytic subunit of serine/threonine protein phosphatase 4 (PP4c). [Tesi di dottorato] (Inedito)
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This dissertation aims to understand the role of CCDC6, a gene frequently rearranged with RET in papillary thyroid carcinoma, in the signal transduction pathway activated by DNA damage. The maintenance of genomic stability is beneficial for the survival of an individual cell and crucial for cancer avoidance. Cells invest huge resources to maintain genomic stability, and cancer cells undergo an array of genetic changes to escape these barriers. The initiation of carcinogenesis represents a mutational event, which in most instances occurs despite functional DNA damage response (DDR) mechanisms. The experiments proposed in this dissertation are aimed to further investigate the mechanisms of chromosomal instability in tumor development. In particular, we will investigate the consequences of CCDC6 gene product loss or inactivation in the carcinogenetic process. CCDC6 gene product is a ubiquitously expressed 65KDa nuclear and cytosolic protein, recognised as a pro-apoptotic phosphoprotein that negatively regulates CREB1-dependent transcription. CCDC6 has been ascribed to the bona fide ATM substrates in response to genotoxic stress. Proteomic screening predicted the interaction between CCDC6 gene product and PP4c, the catalytic subunit of Protein Phosphatase 4, identified as the H2AX phosphatase required for recovery from the DNA damage checkpoint. We reported that, following low doses of genotoxic stress, the loss or inactivation of CCDC6, as occurs in several human cancers carrying the CCDC6 fusion proteins, increases the PP4c dependent dephosphorylation of H2AX, resulting in a deficient DNA damage checkpoint recovery and premature release from G2/M checkpoint arrest. Moreover, we found that the loss of CCDC6 function affects DSBs repair. Our results indicate that CCDC6 is a stress response protein that sustains DNA damage checkpoint and contributes to genome stability maintenance in response to DNA damage by modulating PP4c activity. Overall we believe that in primary tumours the loss of CCDC6 function might contribute to the carcinogenetic process.
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