H2AX Haploinsufficiency Modifies Genomic Stability and Tumor Susceptibility

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2003 Aug 14

PMID 12914701

Citations 236

Authors

Arkady Celeste

Simone Difilippantonio

Michael J Difilippantonio

Oscar Fernandez-Capetillo

Duane R Pilch

Olga A Sedelnikova

Michael Eckhaus

Thomas Ried

William M Bonner

Andre Nussenzweig

Affiliations

Soon will be listed here.

Abstract

Histone H2AX becomes phosphorylated in chromatin domains flanking sites of DNA double-strand breakage associated with gamma-irradiation, meiotic recombination, DNA replication, and antigen receptor rearrangements. Here, we show that loss of a single H2AX allele compromises genomic integrity and enhances the susceptibility to cancer in the absence of p53. In comparison with heterozygotes, tumors arise earlier in the H2AX homozygous null background, and H2AX(-/-) p53(-/-) lymphomas harbor an increased frequency of clonal nonreciprocal translocations and amplifications. These include complex rearrangements that juxtapose the c-myc oncogene to antigen receptor loci. Restoration of the H2AX null allele with wild-type H2AX restores genomic stability and radiation resistance, but this effect is abolished by substitution of the conserved serine phosphorylation sites in H2AX with alanine or glutamic acid residues. Our results establish H2AX as genomic caretaker that requires the function of both gene alleles for optimal protection against tumorigenesis.

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References

Venkatachalam S, Shi Y, Jones S, Vogel H, Bradley A, Pinkel D . Retention of wild-type p53 in tumors from p53 heterozygous mice: reduction of p53 dosage can promote cancer formation. EMBO J. 1998; 17(16):4657-67. PMC: 1170795. DOI: 10.1093/emboj/17.16.4657. View

Fernandez-Capetillo O, Mahadevaiah S, Celeste A, Romanienko P, Camerini-Otero R, Bonner W . H2AX is required for chromatin remodeling and inactivation of sex chromosomes in male mouse meiosis. Dev Cell. 2003; 4(4):497-508. DOI: 10.1016/s1534-5807(03)00093-5. View

Celeste A, Fernandez-Capetillo O, Kruhlak M, Pilch D, Staudt D, Lee A . Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks. Nat Cell Biol. 2003; 5(7):675-9. DOI: 10.1038/ncb1004. View

Paques F, Haber J . Multiple pathways of recombination induced by double-strand breaks in Saccharomyces cerevisiae. Microbiol Mol Biol Rev. 1999; 63(2):349-404. PMC: 98970. DOI: 10.1128/MMBR.63.2.349-404.1999. View

Goss K, Risinger M, Kordich J, Sanz M, Straughen J, Slovek L . Enhanced tumor formation in mice heterozygous for Blm mutation. Science. 2002; 297(5589):2051-3. DOI: 10.1126/science.1074340. View

Agrawal A, Schatz D . RAG1 and RAG2 form a stable postcleavage synaptic complex with DNA containing signal ends in V(D)J recombination. Cell. 1997; 89(1):43-53. DOI: 10.1016/s0092-8674(00)80181-6. View

Downs J, Lowndes N, Jackson S . A role for Saccharomyces cerevisiae histone H2A in DNA repair. Nature. 2001; 408(6815):1001-4. DOI: 10.1038/35050000. View

Inoue K, Zindy F, Randle D, Rehg J, Sherr C . Dmp1 is haplo-insufficient for tumor suppression and modifies the frequencies of Arf and p53 mutations in Myc-induced lymphomas. Genes Dev. 2001; 15(22):2934-9. PMC: 312824. DOI: 10.1101/gad.929901. View

Gladdy R, Taylor M, Williams C, Grandal I, Karaskova J, Squire J . The RAG-1/2 endonuclease causes genomic instability and controls CNS complications of lymphoblastic leukemia in p53/Prkdc-deficient mice. Cancer Cell. 2003; 3(1):37-50. DOI: 10.1016/s1535-6108(02)00236-2. View

10.

Desiderio S, Lin W, Li Z . The cell cycle and V(D)J recombination. Curr Top Microbiol Immunol. 1996; 217:45-59. DOI: 10.1007/978-3-642-50140-1_4. View

11.

Lou Z, Minter-Dykhouse K, Wu X, Chen J . MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways. Nature. 2003; 421(6926):957-61. DOI: 10.1038/nature01447. View

12.

Nussenzweig A, Chen C, da Costa Soares V, Sanchez M, SOKOL K, Nussenzweig M . Requirement for Ku80 in growth and immunoglobulin V(D)J recombination. Nature. 1996; 382(6591):551-5. DOI: 10.1038/382551a0. View

13.

Bassing C, Swat W, Alt F . The mechanism and regulation of chromosomal V(D)J recombination. Cell. 2002; 109 Suppl:S45-55. DOI: 10.1016/s0092-8674(02)00675-x. View

14.

Weaver Z, McCormack S, Liyanage M, Du Manoir S, Coleman A, Schrock E . A recurring pattern of chromosomal aberrations in mammary gland tumors of MMTV-cmyc transgenic mice. Genes Chromosomes Cancer. 1999; 25(3):251-60. View

15.

Bassing C, Suh H, Ferguson D, Chua K, Manis J, Eckersdorff M . Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors. Cell. 2003; 114(3):359-70. DOI: 10.1016/s0092-8674(03)00566-x. View

16.

Gao Y, Ferguson D, Xie W, Manis J, Sekiguchi J, Frank K . Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development. Nature. 2000; 404(6780):897-900. DOI: 10.1038/35009138. View

17.

Quon K, Berns A . Haplo-insufficiency? Let me count the ways. Genes Dev. 2001; 15(22):2917-21. DOI: 10.1101/gad.949001. View

18.

Goldberg M, Stucki M, Falck J, DAmours D, Rahman D, Pappin D . MDC1 is required for the intra-S-phase DNA damage checkpoint. Nature. 2003; 421(6926):952-6. DOI: 10.1038/nature01445. View

19.

Hiom K, Gellert M . Assembly of a 12/23 paired signal complex: a critical control point in V(D)J recombination. Mol Cell. 1998; 1(7):1011-9. DOI: 10.1016/s1097-2765(00)80101-x. View

20.

Sharpless N, Ferguson D, OHagan R, Castrillon D, Lee C, Farazi P . Impaired nonhomologous end-joining provokes soft tissue sarcomas harboring chromosomal translocations, amplifications, and deletions. Mol Cell. 2002; 8(6):1187-96. DOI: 10.1016/s1097-2765(01)00425-7. View