Abstract
There is a gap between the initial formation of cells carrying radiation-induced genetic damage and their contribution to cancer development. Herein, we reveal a previously uncharacterized gene FATS through a genome-wide approach and demonstrate its essential role in regulating the abundance of p21 in surveillance of genome integrity. A large exon coding the NH2-terminal domain of FATS, deleted in spontaneous mouse lymphomas, is much more frequently deleted in radiation-induced mouse lymphomas. Its human counterpart is a fragile site gene at a previously identified loss of heterozygosity site. FATS is essential for maintaining steady-state level of p21 protein and sustaining DNA damage checkpoint. Furthermore, the NH2-terminal FATS physically interacts with histone deacetylase 1 (HDAC1) to enhance the acetylation of endogenous p21, leading to the stabilization of p21. Our results reveal a molecular linkage between p21 abundance and radiation-induced carcinogenesis.
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References
Abbas T, Dutta A . (2009). p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 9: 400–414.
Barboza JA, Liu G, Ju Z, El-Naggar AK, Lozano G . (2006). p21 delays tumor onset by preservation of chromosomal stability. Proc Natl Acad Sci USA 103: 19842–19847.
Bendiennat M, Boulaire J, Jascur T, Brickner H, Barbier V, Sarasin A et al. (2003). UV irradiation triggers ubiquitin-dependent degradation of p21(WAF1) to promoter DNA repair. Cell 114: 599–610.
Bichara M, Wagner J, Lambert IB . (2006). Mechanisms of tandem repeat instability in bacteria. Mut Res 598: 144–163.
Bloom J, Amador V, Bartolini F, DeMartino G, Pagano M . (2003). Proteasome-mediated degradation of p21via N-terminal ubiquitinylation. Cell 115: 71–82.
Brenner DJ, Doll R, Goodhead DT, Hall EJ, Land CE, Little JB et al. (2003). Cancer risks attributable to low doses of ionizing radiation: assessing what we really know. Proc Natl Acad Sci USA 100: 13761–13766.
Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T, Hannon GJ . (1995). Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 377: 552–557.
Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown JP et al. (1998). Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282: 1497–1501.
Buttel I, Fechter A, Schwab M . (2004). Common fragile sites and cancer: targeted cloning by insertional mutagenesis. Ann NY Acad Sci 1028: 14–27.
Cai WW, Mao JH, Chow CW, Damani S, Balmain A, Bradley A . (2002). Genome-wide detection of chromosomal imbalances in tumors using BAC microarrays. Nat Biotechnol 20: 393–396.
Casper AM, Nghiem P, Arlt MF, Glover TW . (2002). ATR regulates fragile site stability. Cell 111: 779–789.
Cen B, Deguchi A, Weinstein IB . (2008). Activation of protein kinase G increases the expression of p21CIP1, p27KIP1, and histidine triad protein 1 through Sp1. Cancer Res 68: 5355–5362.
Chen X, Chi Y, Bloecher A, Aebersold R, Clurman BE, Roberts JM . (2004). N-acetylation and ubiquitin-independent proteasomal degradation of p21(Cip1). Mol Cell 16: 839–847.
Chen X, Barton LF, Chi Y, Clurman BE, Roberts JM . (2007). Ubiquitin-independent degradation of cell-cycle inhibitos by the REGγ proteasome. Mol Cell 26: 843–852.
Coulombe P, Rodier G, Bonneil E, Thibault P, Meloche S . (2004). N-terminal ubiquitination of extracellular signal-regulated kinase 3 and p21 directs their degradation by the proteasome. Mol Cell Biol 24: 6140–6150.
Deng C, Zhang P, Harper JW, Elledge SJ, Leder P . (1995). Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 82: 675–684.
DiTullio Jr RA, Mochan TA, Venere M, Bartkova J, Sehested M, Bartek J et al. (2002). 53BP1 functions in an ATM-dependent checkpoint pathway that is constitutively activated in human cancer. Nat Cell Biol 4: 998–1002.
Dokmanovic M, Clarke C, Marks PA . (2007). Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res 5: 981–989.
Durkin SG, Glover TW . (2007). Chromosome fragile sites. Annu Rev Genet 41: 169–192.
Efeyan A, Collado M, Velasco-Miguel S, Serrano M . (2007). Genetic dissection of the role of p21Cip1/Waf1 in p53-mediated tumor suppression. Oncogene 26: 1645–1649.
Glover TW, Arlt MF, Casper AM, Durkin SG . (2005). Mechanisms of common fragile site instability. Hum Mol Genet 14: R197–R205.
Holm LE . (1990). Cancer occurring after radiotherapy and chemotherapy. Int J Radiat Oncol Biol Phy 19: 1303–1308.
Hoppe-Seyler F, Butz K . (1993). Repression of endogenous p53 transactivation function in HeLa cervical carcinoma cells by human papillomavirus type 16 E6, human mdm-2, and mutant p53. J Virol 67: 3111–3117.
Johnstone RW . (2002). Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov 1: 287–299.
Kastan MB, Bartek J . (2004). Cell-cycle checkpoints and cancer. Nature 432: 316–323.
Kemp CJ, Wheldon T, Balmain A . (1994). p53-deficient mice are extremely susceptible to radiation-induced tumorigenesis. Nat Genet 8: 66–69.
Kim GD, Choi YH, Dimtchev A, Jeong SJ, Dritschilo A, Jung M . (1999). Sensing of ionizing radiation-induced DNA damage by ATM through interaction with histone deacetylase. J Biol Chem 274: 31127–31130.
Lagger G, O'Carroll D, Rembold M, Khier H, Tischler J, Weitzer G et al. (2002). Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. EMBO J 21: 2672–2681.
Li X, Amazit L, Long W, Lonard DM, Monaco JJ, O'Malley BW . (2007). Ubiquitin- and ATP-independent proteolytic turnover of p21 by the REGγ-proteasome pathway. Mol Cell 26: 831–842.
Li Z, Day CP, Yang JY, Tsai WB, Lozano G, Shih HM et al. (2004). Adenoviral E1A targets Mdm4 to stabilize tumor suppressor p53. Cancer Res 64: 9080–9085.
Liehr T, Heller A, Starke H, Claussen U . (2002). FISH banding methods: applications in research and diagnosis. Expert Rev Mol Diagn 2: 217–225.
Lin RJ, Nagy L, Inoue S, Shao W, Miller WH, Evans RM . (1998). Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature 391: 811–814.
Macleod KF, Sherry N, Hannon G, Beach D, Tokino T, Kinzler K et al. (1995). P 53-dependent and independent expression of p21 during cell growth, differentiation, and DNA damage. Genes Dev 9: 935–944.
Magrath IT . (1997). The treatment of pediatric lymphomas: paradigms to plagiarize? Ann Oncol 8: 7–14.
Maier D, Comparone D, Taylor E, Zhang Z, Gratzl O, van Meir EG et al. (1997). New deletion in low-grade oligodendroglioma at the glioblastoma suppressor locus on chromosome 10q25-26. Oncogene 15: 997–1000.
Mangelsdorf M, Ried K, Woollatt E, Dayan S, Eyre H, Finnis M et al. (2000). Chromosomal fragile site FRA16D and DNA instability in cancer. Cancer Res 60: 1683–1689.
Mao JH, Li J, Jiang T, Li Q, Wu D, Perez-Losada J et al. (2005). Genomic instability in radiation-induced mouse lymphoma from p53 heterozygous mice. Oncogene 24: 7924–7934.
Martin-Caballero J, Flores JM, Garcia-Palencia P, Serrano M . (2001). Tumor susceptibility of p21(Waf1/Cip1)-deficient mice. Cancer Res 61: 6234–6238.
Maser RS, DePinho RA . (2002). Connecting chromosomes, crisis, and cancer. Science 297: 565–569.
Nagase S, Yamakawa H, Sato S, Yajima A, Horii A . (1997). Identification of a 790-kilobase region of common allelic loss in chromosome 10q25-q26 in human endometrial cancer. Cancer Res 57: 1630–1633.
Ohi R, Gould KL . (1999). Regulating the onset of mitosis. Curr Opin Cell Biol 11: 267–273.
Pagano M, Tam SW, Theodoras AM, Beer-Romero P, Del Sal G, Chau V et al. (1995). Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 269: 682–685.
Pearson CE, edamura KN, Cleary JD . (2005). Repeat instability: mechanisms of dynamic mutations. Nat Rev Genet 6: 729–742.
Rouse J, Jackson SP . (2002). Interfaces between the detection, signaling, and repair of DNA damage. Science 297: 547–551.
Schellong G . (1998). Pediatric Hodgkin's disease: treatment in the late 1990s. Ann Oncol 9: S115–S119.
Sherr CJ, Roberts TM . (1999). CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13: 1501–1512.
Shiloh Y . (2003). ATM and related protein kinase: safeguarding genome integrity. Nat Rev Cancer 3: 155–168.
Schwartz M, Zlotorynski E, Kerem B . (2006). The molecular basis of common and rare fragile sites. Cancer Lett 232: 13–26.
Sheaff RJ, Singer JD, Swanger J, Smitherman M, Roberts JM, Clurman BE . (2000). Proteasomal turnover of p21Cip1 does not require p21Cip1 ubiquitination. Mol Cell 5: 403–410.
Touitou R, Richardson J, Bose S, Nakanishi M, Rivett J, Allday MJ . (2001). A degradation signal located in the C-terminus of p21WAF1/CIP1 is a binding site for the C8 alpha-subunit of the 20S proteasome. EMBO J 20: 2367–2375.
Van Gent DC, Hoeijmakers JH, Kanaar R . (2001). Chromosomal stability and the DNA double-stranded break connection. Nat Rev Genet 2: 196–206.
Varshavsky A, Turner G, Du F, Xie Y . (2000). Felix HoppeSeyler Lecture 2000. The ubiquitin system and the N-end rule pathway. Biol Chem 381: 779–789.
Wei Q, Miskimins WK, Miskimins R . (2003). The Sp1 family of transcription factor is involved in p27(Kip1)-mediated activation of myelin basic protein gene expression. Mol Cell Biol 23: 4035–4045.
Winter ZE, Leek RD, Bradburn MJ, Norbury CJ, Harris AL . (2003). Cytoplasmic p21WAF1/CIP1 expression is correlated with HER-2/neu in breast cancer and is an independent predictor of prognosis. Breast Cancer Res 5: R242–R249.
Xia W, Chen JS, Zhou X, Sun PR, Lee DF, Liao Y et al. (2004). Phosphorylation/cytoplasmic localization of p21C/p1/WAF1 is associated with HER2/neu overexpression and provided a novel combination predictor for poor prognosis in breast cancer patients. Clin Cancer Res 10: 3815–3824.
Zhang H, Freudenreich CH . (2007). An AT-rich sequence in human common fragile site FRA16D causes fork stalling and chromosome breakage in S. cerevisiae. Mol Cell 27: 367–379.
Zhou BP, Liao Y, Xia W, Spohn B, Lee MH, Hung MC . (2001). Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nat Cell Biol 3: 245–252.
Zupkovitz G, Tischler J, Posch M, Sadzak I, Ramsauer K, Egger G et al. (2006). Negative and positive regulation of gene expression by mouse histone deacetylase 1. Mol Cell Biol 26: 7913–7928.
Acknowledgements
We are grateful to Mien-Chi Hung for critical discussions. We thank Xiangwei He and Qi Gao for assistance in microscopic imaging; Tao Jiang and Qian Li for technical assistance. This study was supported in part by the following grants: Tianjin Medical University Cancer Institute and Hospital Start-up 08Y01 (to Z Li); Ministry of Science and Technology of China 973-program Concept Award 2009CB526407 (to Z Li); Tianjin Municipal Science and Technology Foundation (to Z Li); Department of defense of United States FG02-03ER63630 (to A Balmain); IZKF Jena Start-up S16 (to T Liehr).
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Li, Z., Zhang, Q., Mao, JH. et al. An HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis. Oncogene 29, 2659–2671 (2010). https://doi.org/10.1038/onc.2010.19
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DOI: https://doi.org/10.1038/onc.2010.19
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