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H2AFX (H2A histone family, member X)

Written2009-03Niloo Srivastava, Sailesh Gochhait, P Kalaiarasan, Rameshwar NK Bamezai
National center of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India

(Note : for Links provided by Atlas : click)


Alias (NCBI)H2A.X
LocusID (NCBI) 3014
Atlas_Id 40783
Location 11q23.3  [Link to chromosome band 11q23]
Location_base_pair Starts at and ends at bp from pter
Local_order According to NCBI Map Viewer, genes from centromere to telomere direction with respect to H2AFX, on 11q23 are: hypoxia up-regulated 1 (HYOU1), vacuolar protein sorting 11 homolog (S. cerevisiae) (VPS11), hydroxymethylbilane synthase (HMBS), H2A histone family, member X (H2AFX), dolichyl-phosphate (UDP-N-acetylglucosamine) N-acetylglucosaminephosphotransferase 1 (GlcNAc-1-P transferase) (DPAGT1), transmembrane protein 24 (TMEM 24), MBD2-interacting zinc finger (MIZF).
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
H2AFX (11q23.3)::ATG12 (5q22.3)H2AFX (11q23.3)::WDR18 (19p13.3)WDR18 (19p13.3)::H2AFX (11q23.3)
Note Histone H2AX is a variant of histone H2A and it constitutes ~ 15-20% of total histone H2A pool. It differs from H2A in the presence of evolutionary conserved C-terminal tail that gets phosphorylated at serine 140 residue in response to genomic insult and also in response to certain stress (heat, hypoxia and changes in osmolarity).


Note H2AFX gene sequence is highly GC rich and lies in the CpG island (118470228-11847164) with a ratio of observed to expected CpG 1.02.
  Figure 1: Gene Structure of H2AFX.
Description According to Entrez-Gene, H2AFX gene maps to NC 000011.8 in the region between 118469794 and 118471387 on the minus strand. It is a small gene (DQ015918) having a single exon of 432 nucleotides, 73 bp 5'UTR and 1089 bp 3'UTR. It contains no introns.
H2AFX is recognized as an important DNA damage response (DDR) gene. It maps to cytogenetic locus 11q23.2-23.3 that is highly represented among those commonly deleted or translocated in several haematological malignancies or solid tumors. Interestingly other key DNA damage response genes in the region are ATM, MRE11 and CHK1; combined loss of which can be detrimental to the cell.
Transcription Histone H2AFX mRNA (NM_002105) has 1594 bp and is synthesized in G1 as well as S phase. It is known to have two forms of transcript; one having a polyA tail (1651 bp) and another having a conserved stem-loop and U7 binding sequences involved in the processing and stability of replication type histone mRNAs (575 bp).
Pseudogene No pseudogene for H2AFX is known.


Note The C-terminal tail of H2AX is highly conserved along with the SQ-motif that gets phosphorylated at the serine residue by members of phosphoinositide 3-kinase related protein kinases (PIKKs).
  Figure 2 : Protein Structure of histone H2AX protein.
Description A single exon having a length of 432 nucleotides codes for H2AX protein of molecular weight 15 kDA. It has a characteristic histone H2A domain ranging from 18 to 91 amino acid with H2A signature motif from 22-28 aa. The SQ-motif (140-141) is a feature of H2AX variant that differentiates it from rest of the members of H2A family. The H2AX protein undergoes several posttranslational modifications either in constitutive manner like monoubiquitination at lysine 120 or in response to cellular stress/DNA damage, like acetylation of lysine 5 and phosphorylation of serine 140 and tyrosine 143 residues. By virtue of these posttranslational events, H2AX acquires new regulatory functions during DNA repair and other metabolic processes.
Expression H2AX is ubiquitously expressed in humans with the highest levels observed in the proliferating tissues, eg., testis and thymus. Phosphorylated H2AX is widely correlated with the extent of DNA damage and forms discrete nuclear foci at the sites of damage.
Localisation Located in the nucleus and forms discrete foci upon DNA damage.
The figure 3 shows typical staining of H2AX and gamma H2AX in HeLa cells before and after the treatment with etoposide (10mM).
  Figure 3
Function Phosphorylation of Ser-140 (known as gamma-H2AX) is critical during DNA double-strand break signaling. Apart from the exogeneous agents (radiation and chemicals), DSBs generated during replication fork stalling, meiotic recombination events and during immunoglobulin class switching in lymphocytes are also known to induce the formation of gamma H2AX. This phosphorylation event can extend up to 1 megabase on either side of DSB, amplifying the damage signal and hence facilitating recruitment of repair proteins and accomplishment of repair process. The kinases responsible for the serine phosphorylation are ATM, ATR and DNA-PKcs. Once the repair is complete, dephosphorylation of Ser-140 is mediated by a phosphatase, PP2A.
During meiosis, programmed DSBs are formed in SPO-11 dependent manner and H2AX-Ser-140 phosphorylation has been shown to accumulate at synaptonemal complexes. With the progression from leptotene to zygotene and pachytene, the gamma H2AX is subsequently seen sequestered at unsynapsed regions of autosomes and also in the XY-body, probably required for meiotic sex chromosome inactivation. (MSCI).
Apart from ser-140 phosphorylation, the protein also gets modified at lysine 5 residue by TIP60 mediated acetylation and subsequent ubiquitination by UBC-13 in response to DNA damage. The functional implication of this modification is not very clear although it is suggested that this helps in chromatin modulation during the repair process.
Tyrosine 143 phosphorylation of H2AX by WSTF having a tyrosine kinase activity and a component of WICH ATP-dependent chromatin remodeling complex was recently shown to be critical during DNA damage response and acts as a switch to apoptosis/cell survival.
No mutation in H2AFX gene has been detected so far. Few direct studies on human cancers, one on 101 familial breast cancer samples, another on 112 tumors from seven different B cell leukemia/lymphoma and yet another on sporadic breast cancer patients failed to identify any change at nucleotide level. A partial deletion of the region encompassing H2AFX was however identified in significant proportion of head and neck squamous cell carcinoma.
Homology The sequence of 22 residues at carboxy terminal of H2AX is unique and is unrelated to any of the H2A family member but is highly conserved and is present in all eukaryotes.


Note No mutation so far has been reported for H2AFX.

Implicated in

Entity Various cancers
Note Histone H2AX has been implicated in different human cancers based on association studies of polymorphisms found in the promoter region of the gene. SNPs in the far promoter region of H2AFX (rs643788, rs8551 and rs7759, rs2509049) has been shown to be associated with the risk of sporadic breast cancer and Non-Hodgkin's Lymphomas but no association was observed in case of bladder carcinoma. Also alteration of H2AFX gene copy number in significant proportion (37%) of sporadic breast cancer patients has been reported.


DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis.
Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F, Zieger K, Guldberg P, Sehested M, Nesland JM, Lukas C, Orntoft T, Lukas J, Bartek J.
Nature. 2005 Apr 14;434(7035):864-70.
PMID 15829956
Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors.
Bassing CH, Suh H, Ferguson DO, Chua KF, Manis J, Eckersdorff M, Gleason M, Bronson R, Lee C, Alt FW.
Cell. 2003 Aug 8;114(3):359-70.
PMID 12914700
H2AX haploinsufficiency modifies genomic stability and tumor susceptibility.
Celeste A, Difilippantonio S, Difilippantonio MJ, Fernandez-Capetillo O, Pilch DR, Sedelnikova OA, Eckhaus M, Ried T, Bonner WM, Nussenzweig A.
Cell. 2003 Aug 8;114(3):371-83.
PMID 12914701
Genomic instability in mice lacking histone H2AX.
Celeste A, Petersen S, Romanienko PJ, Fernandez-Capetillo O, Chen HT, Sedelnikova OA, Reina-San-Martin B, Coppola V, Meffre E, Difilippantonio MJ, Redon C, Pilch DR, Olaru A, Eckhaus M, Camerini-Otero RD, Tessarollo L, Livak F, Manova K, Bonner WM, Nussenzweig MC, Nussenzweig A.
Science. 2002 May 3;296(5569):922-7. Epub 2002 Apr 4.
PMID 11934988
Response to RAG-mediated VDJ cleavage by NBS1 and gamma-H2AX.
Chen HT, Bhandoola A, Difilippantonio MJ, Zhu J, Brown MJ, Tai X, Rogakou EP, Brotz TM, Bonner WM, Ried T, Nussenzweig A.
Science. 2000 Dec 8;290(5498):1962-5.
PMID 11110662
Analysis of variants in DNA damage signalling genes in bladder cancer.
Choudhury A, Elliott F, Iles MM, Churchman M, Bristow RG, Bishop DT, Kiltie AE.
BMC Med Genet. 2008 Jul 18;9:69.
PMID 18638378
gamma-H2AX dephosphorylation by protein phosphatase 2A facilitates DNA double-strand break repair.
Chowdhury D, Keogh MC, Ishii H, Peterson CL, Buratowski S, Lieberman J.
Mol Cell. 2005 Dec 9;20(5):801-9. Epub 2005 Nov 28.
PMID 16310392
Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions.
Cook PJ, Ju BG, Telese F, Wang X, Glass CK, Rosenfeld MG.
Nature. 2009 Apr 2;458(7238):591-6. Epub 2009 Feb 22.
PMID 19234442
Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions.
Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A, Liloglou T, Venere M, Ditullio RA Jr, Kastrinakis NG, Levy B, Kletsas D, Yoneta A, Herlyn M, Kittas C, Halazonetis TD.
Nature. 2005 Apr 14;434(7035):907-13.
PMID 15829965
A phosphatase complex that dephosphorylates gammaH2AX regulates DNA damage checkpoint recovery.
Keogh MC, Kim JA, Downey M, Fillingham J, Chowdhury D, Harrison JC, Onishi M, Datta N, Galicia S, Emili A, Lieberman J, Shen X, Buratowski S, Haber JE, Durocher D, Greenblatt JF, Krogan NJ.
Nature. 2006 Jan 26;439(7075):497-501. Epub 2005 Nov 20.
PMID 16299494
Acetylation by Tip60 is required for selective histone variant exchange at DNA lesions.
Kusch T, Florens L, Macdonald WH, Swanson SK, Glaser RL, Yates JR 3rd, Abmayr SM, Washburn MP, Workman JL.
Science. 2004 Dec 17;306(5704):2084-7. Epub 2004 Nov 4.
PMID 15528408
Genetic variants in the H2AFX promoter region are associated with risk of sporadic breast cancer in non-Hispanic white women aged
Lu J, Wei Q, Bondy ML, Brewster AM, Bevers TB, Yu TK, Buchholz TA, Meric-Bernstam F, Hunt KK, Singletary SE, Wang LE.
Breast Cancer Res Treat. 2008 Jul;110(2):357-66. Epub 2007 Sep 13.
PMID 17851762
Recombinational DNA double-strand breaks in mice precede synapsis.
Mahadevaiah SK, Turner JM, Baudat F, Rogakou EP, de Boer P, Blanco-Rodriguez J, Jasin M, Keeney S, Bonner WM, Burgoyne PS.
Nat Genet. 2001 Mar;27(3):271-6.
PMID 11242108
Absence of constitutional H2AX gene mutations in 101 hereditary breast cancer families.
Monteiro AN, Zhang S, Phelan CM, Narod SA.
J Med Genet. 2003 Apr;40(4):e51.
PMID 12676924
Genetic variation in H2AFX contributes to risk of non-Hodgkin lymphoma.
Novik KL, Spinelli JJ, Macarthur AC, Shumansky K, Sipahimalani P, Leach S, Lai A, Connors JM, Gascoyne RD, Gallagher RP, Brooks-Wilson AR.
Cancer Epidemiol Biomarkers Prev. 2007 Jun;16(6):1098-106.
PMID 17548670
Loss of distal 11q is associated with DNA repair deficiency and reduced sensitivity to ionizing radiation in head and neck squamous cell carcinoma.
Parikh RA, White JS, Huang X, Schoppy DW, Baysal BE, Baskaran R, Bakkenist CJ, Saunders WS, Hsu LC, Romkes M, Gollin SM.
Genes Chromosomes Cancer. 2007 Aug;46(8):761-75.
PMID 17492757
DNA-PK is responsible for enhanced phosphorylation of histone H2AX under hypertonic conditions.
Reitsema T, Klokov D, Banath JP, Olive PL.
DNA Repair (Amst). 2005 Sep 28;4(10):1172-81.
PMID 16046194
Megabase chromatin domains involved in DNA double-strand breaks in vivo.
Rogakou EP, Boon C, Redon C, Bonner WM.
J Cell Biol. 1999 Sep 6;146(5):905-16.
PMID 10477747
Role of H2AX in DNA damage response and human cancers.
Srivastava N, Gochhait S, de Boer P, Bamezai RN.
Mutat Res. 2009 Mar-Jun;681(2-3):180-8. Epub 2008 Aug 29.
PMID 18804552
Absence of H2AX gene mutations in B-cell leukemias and lymphomas.
Walsh SH, Rosenquist R.
Leukemia. 2005 Mar;19(3):464.
PMID 15674416
WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase activity.
Xiao A, Li H, Shechter D, Ahn SH, Fabrizio LA, Erdjument-Bromage H, Ishibe-Murakami S, Wang B, Tempst P, Hofmann K, Patel DJ, Elledge SJ, Allis CD.
Nature. 2009 Jan 1;457(7225):57-62. Epub 2008 Dec 17.
PMID 19092802


This paper should be referenced as such :
Srivastava, N ; Gochhait, S ; Kalaiarasan, P ; Bamezai, RNK
H2AFX (H2A histone family, member X)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(2):117-120.
Free journal version : [ pdf ]   [ DOI ]

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 4 ]
  t(11;19)(q23;p13) H2AFX::WDR18
t(11;19)(q23;p13) WDR18::H2AFX
t(11;19)(q23;p13) H2AFX::WDR18
t(11;19)(q23;p13) WDR18::H2AFX

External links

Atlas Explorer : (Salamanque)
Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
BioGPS (Tissue expression)3014
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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