TY - JOUR
T1 - Mutations in CREBBP and EP300 genes affect DNA repair of oxidative damage in Rubinstein-Taybi syndrome cells
AU - Dutto, Ilaria
AU - Scalera, Claudia
AU - Tillhon, Micol
AU - Ticli, Giulio
AU - Passaniti, Gianluca
AU - Cazzalini, Ornella
AU - Savio, Monica
AU - Stivala, Lucia A.
AU - Gervasini, Cristina
AU - Larizza, Lidia
AU - Prosperi, Ennio
N1 - Funding Information:
This work in part was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC, grants IG 11747 and 17041) to E.P., and by ‘University of Milan young researcher’ grant to C.G. (Dotazione d’ateneo linea 2 del piano di sostegno alla ricerca).
Funding Information:
We thank the patients’ families for participating in this study and the Italian Association of Rubinstein-Taybi patients ‘RTS Una Vita Speciale ONLUS’ for continual support. We also thank prof. R.H. Goodman (Oregon University) for providing the CBP plasmid. The ‘Galliera Genetic Bank’, member of the Telethon Network of Genetic Biobanks (project no. GTB12001), funded by Telethon Italy, and of the EuroBioBank network, provided us with cell lines.
Publisher Copyright:
© 2019 The Author(s). Published by Oxford University Press. All rights reserved.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/5/14
Y1 - 2020/5/14
N2 - Rubinstein-Taybi syndrome (RSTS) is an autosomal-dominant disorder characterized by intellectual disability, skeletal abnormalities, growth deficiency and an increased risk of tumors. RSTS is predominantly caused by mutations in CREBBP or EP300 genes encoding for CBP and p300 proteins, two lysine acetyl-transferases (KAT) playing a key role in transcription, cell proliferation and DNA repair. However, the efficiency of these processes in RSTS cells is still largely unknown. Here, we have investigated whether pathways involved in the maintenance of genome stability are affected in lymphoblastoid cell lines (LCLs) obtained from RSTS patients with mutations in CREBBP or in EP300 genes. We report that RSTS LCLs with mutations affecting CBP or p300 protein levels or KAT activity, are more sensitive to oxidative DNA damage and exhibit defective base excision repair (BER). We have found reduced OGG1 DNA glycosylase activity in RSTS compared to control cell extracts, and concomitant lower OGG1 acetylation levels, thereby impairing the initiation of the BER process. In addition, we report reduced acetylation of other BER factors, such as DNA polymerase ß and Proliferating Cell Nuclear Antigen (PCNA), together with acetylation of histone H3. We also show that complementation of CBP or p300 partially reversed RSTS cell sensitivity to DNA damage. These results disclose a mechanism of defective DNA repair as a source of genome instability in RSTS cells.
AB - Rubinstein-Taybi syndrome (RSTS) is an autosomal-dominant disorder characterized by intellectual disability, skeletal abnormalities, growth deficiency and an increased risk of tumors. RSTS is predominantly caused by mutations in CREBBP or EP300 genes encoding for CBP and p300 proteins, two lysine acetyl-transferases (KAT) playing a key role in transcription, cell proliferation and DNA repair. However, the efficiency of these processes in RSTS cells is still largely unknown. Here, we have investigated whether pathways involved in the maintenance of genome stability are affected in lymphoblastoid cell lines (LCLs) obtained from RSTS patients with mutations in CREBBP or in EP300 genes. We report that RSTS LCLs with mutations affecting CBP or p300 protein levels or KAT activity, are more sensitive to oxidative DNA damage and exhibit defective base excision repair (BER). We have found reduced OGG1 DNA glycosylase activity in RSTS compared to control cell extracts, and concomitant lower OGG1 acetylation levels, thereby impairing the initiation of the BER process. In addition, we report reduced acetylation of other BER factors, such as DNA polymerase ß and Proliferating Cell Nuclear Antigen (PCNA), together with acetylation of histone H3. We also show that complementation of CBP or p300 partially reversed RSTS cell sensitivity to DNA damage. These results disclose a mechanism of defective DNA repair as a source of genome instability in RSTS cells.
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U2 - 10.1093/carcin/bgz149
DO - 10.1093/carcin/bgz149
M3 - Article
C2 - 31504229
AN - SCOPUS:85084692713
VL - 41
SP - 257
EP - 266
JO - Carcinogenesis
JF - Carcinogenesis
SN - 0143-3334
IS - 3
ER -