DNA damage response defect in Williams-Beuren syndrome

Guenat,David; Merla,Giuseppe; Deconinck,Eric; Borg,Christophe; Rohrlich,Pierre‑Simon

doi:10.3892/ijmm.2017.2861

DNA damage response defect in Williams-Beuren syndrome

Authors:
- David Guenat
- Giuseppe Merla
- Eric Deconinck
- Christophe Borg
- Pierre‑Simon Rohrlich
View Affiliations

Affiliations: Laboratory of Cellular and Molecular Biology, University Hospital of Besançon, F-25000 Besançon, France, Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia I‑71013, Italy, Inserm UMR1098/EFS‑BFC/University of Franche‑Comte, LabEx LipSTIC, F-25000 Besançon, France
Published online on: January 17, 2017 https://doi.org/10.3892/ijmm.2017.2861
Pages: 622-628
Copyright: © Guenat et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Williams-Beuren syndrome (WBS, no. OMIM 194050) is a rare multisystem genetic disorder caused by a microdeletion on chromosome 7q11.23 and characterized by cardiovascular malformations, mental retardation, and a specific facial dysmorphism. Recently, we reported that a series of non‑Hodgkin's lymphoma occurs in children with WBS and thus hypothesized that a predisposition to cancer may be associated with this genetic disorder. The aim of the present study was to ascertain the role played by three genes hemizygously deleted in WBS (RFC2, GTF2I and BAZ1B) in DNA damage response pathways. Cell proliferation, cell cycle analysis, γ‑H2A.X induction, and expression of DNA damage response proteins were investigated upon exposure to genotoxic treatments in WBS patient‑derived primary fibroblasts and in the 293T cell line treated with specific siRNAs targeting RFC2, GTF2I and BAZ1B. An impaired hydroxyurea‑induced phosphorylation of CHK1 was observed in the WBS cells. However, this defective DNA damage response was not associated with an increased sensitivity to genotoxic agents. In addition, depletion of RFC2, GTF2I and BAZ1B using specific siRNAs did not have a significant impact on the DNA damage response in 293T cells. Our results highlight that the ATR‑dependent DNA damage response is impaired in WBS patient cells but is also dispensable for viability when these cells undergo a genotoxic stress. The mechanism by which the ATR pathway is impaired in WBS warrants elucidation through further investigation.

View Figures

View References

1	Pober BR: Williams-Beuren syndrome. N Engl J Med. 362:239–252. 2010. View Article : Google Scholar : PubMed/NCBI
2	Guenat D, Quentin S, Rizzari C, Lundin C, Coliva T, Edery P, Fryssira H, Bermont L, Ferrand C, Soulier J, et al: Constitutional and somatic deletions of the Williams-Beuren syndrome critical region in non-Hodgkin lymphoma. J Hematol Oncol. 7:822014. View Article : Google Scholar : PubMed/NCBI
3	Guenat D, Rizzari C, Lundin C, Borg C, Soulier J and Rohrlich PS: Predisposition to Burkitt lymphoma in Williams-Beuren syndrome. Blood. 124:21822014.
4	Chrzanowska KH, Gregorek H, Dembowska-Bagińska B, Kalina MA and Digweed M: Nijmegen breakage syndrome (NBS). Orphanet J Rare Dis. 7:132012. View Article : Google Scholar : PubMed/NCBI
5	Arora H, Chacon AH, Choudhary S, McLeod MP, Meshkov L, Nouri K and Izakovic J: Bloom syndrome. Int J Dermatol. 53:798–802. 2014. View Article : Google Scholar : PubMed/NCBI
6	Suarez F, Mahlaoui N, Canioni D, Andriamanga C, Dubois d'Enghien C, Brousse N, Jais JP, Fischer A, Hermine O and Stoppa-Lyonnet D: Incidence, presentation, and prognosis of malignancies in ataxia-telangiectasia: A report from the French National Registry of Primary Immune Deficiencies. J Clin Oncol. 33:202–208. 2015. View Article : Google Scholar
7	Attarbaschi A, Carraro E, Abla O, Barzilai-Birenboim S, Bomken S, Brugieres L, Bubanska E, Burkhardt B, Chiang AK, Csoka M, et al: Non-Hodgkin's lymphoma and pre-existing conditions: spectrum, clinical characteristics and outcome in 213 children and adolescents. Haematologica. Aug 11–2016.Epub ahead of print. View Article : Google Scholar
8	Noskov VN, Araki H and Sugino A: The RFC2 gene, encoding the third-largest subunit of the replication factor C complex, is required for an S-phase checkpoint in Saccharomyces cerevisiae. Mol Cell Biol. 18:4914–4923. 1998. View Article : Google Scholar : PubMed/NCBI
9	Desgranges ZP, Ahn J, Lazebnik MB, Ashworth T, Lee C, Pestell RC, Rosenberg N, Prives C and Roy AL: Inhibition of TFII-I-dependent cell cycle regulation by 53. Mol Cell Biol. 25:10940–10952. 2005. View Article : Google Scholar : PubMed/NCBI
10	Tanikawa M, Wada-Hiraike O, Nakagawa S, Shirane A, Hiraike H, Koyama S, Miyamoto Y, Sone K, Tsuruga T, Nagasaka K, et al: Multifunctional transcription factor TFII-I is an activator of BRCA1 function. Br J Cancer. 104:1349–1355. 2011. View Article : Google Scholar : PubMed/NCBI
11	Fattah FJ, Hara K, Fattah KR, Yang C, Wu N, Warrington R, Chen DJ, Zhou P, Boothman DA and Yu H: The transcription factor TFII-I promotes DNA translesion synthesis and genomic stability. PLoS Genet. 10:e10044192014. View Article : Google Scholar : PubMed/NCBI
12	Poot RA, Bozhenok L, van denBerg DLC, Steffensen S, Ferreira F, Grimaldi M, Gilbert N, Ferreira J and Varga-Weisz PD: The Williams syndrome transcription factor interacts with PCNA to target chromatin remodelling by ISWI to replication foci. Nat Cell Biol. 6:1236–1244. 2004. View Article : Google Scholar : PubMed/NCBI
13	Kitagawa H, Fujiki R, Yoshimura K, Oya H and Kato S: Williams syndrome is an epigenome-regulator disease. Endocr J. 58:77–85. 2011. View Article : Google Scholar : PubMed/NCBI
14	Xiao A, Li H, Shechter D, Ahn SH, Fabrizio LA, Erdjument- Bromage H, Ishibe-Murakami S, Wang B, Tempst P, Hofmann K, et al: WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase activity. Nature. 457:57–62. 2009. View Article : Google Scholar
15	Singh N, Basnet H, Wiltshire TD, Mohammad DH, Thompson JR, Héroux A, Botuyan MV, Yaffe MB, Couch FJ, Rosenfeld MG, et al: Dual recognition of phosphoserine and phosphotyrosine in histone variant H2A.X by DNA damage response protein MCPH1. Proc Natl Acad Sci USA. 109:14381–14386. 2012. View Article : Google Scholar : PubMed/NCBI
16	O'Driscoll M, Dobyns WB, van Hagen JM and Jeggo PA: Cellular and clinical impact of haploinsufficiency for genes involved in ATR signaling. Am J Hum Genet. 81:77–86. 2007. View Article : Google Scholar : PubMed/NCBI
17	Savina NV, Smal MP, Kuzhir TD, Egorova TM, Khurs OM, Polityko AD and Goncharova RI: Chromosomal instability at the 7q11.23 region impacts on DNA-damage response in lymphocytes from Williams-Beuren syndrome patients. Mutat Res. 724:46–51. 2011. View Article : Google Scholar : PubMed/NCBI