H2AX_MOUSE - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: H2AX_MOUSE
• UniProt AC: P27661
• Protein Name: Histone H2AX
• Gene Name: H2afx
• Organism: Mus musculus (Mouse).
• Sequence Length: 143
• Subcellular Localization: Nucleus . Chromosome .
• Protein Description: Variant histone H2A which replaces conventional H2A in a subset of nucleosomes. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling. Required for checkpoint-mediated arrest of cell cycle progression in response to low doses of ionizing radiation and for efficient repair of DNA double strand breaks (DSBs) specifically when modified by C-terminal phosphorylation..
• Protein Sequence: MSGRGKTGGKARAKAKSRSSRAGLQFPVGRVHRLLRKGHYAERVGAGAPVYLAAVLEYLTAEILELAGNAARDNKKTRIIPRHLQLAIRNDEELNKLLGGVTIAQGGVLPNIQAVLLPKKSSATVGPKAPAVGKKASQASQEY

Overview of Protein Modification Sites with Functional and Structural Information

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
2	Acetylation	------MSGRGKTGG ------CCCCCCCCC	36.88	7217105
2	Phosphorylation	------MSGRGKTGG ------CCCCCCCCC	36.88	7217105
6	Acetylation	--MSGRGKTGGKARA --CCCCCCCCCHHHH	42.51	23806337
6	Sumoylation	--MSGRGKTGGKARA --CCCCCCCCCHHHH	42.51	28289178
10	Acetylation	GRGKTGGKARAKAKS CCCCCCCHHHHHHHH	35.72	23806337
10	Lactoylation	GRGKTGGKARAKAKS CCCCCCCHHHHHHHH	35.72	-
37	Acetylation	RVHRLLRKGHYAERV HHHHHHHCCCHHHHC	50.43	20488183
51	Phosphorylation	VGAGAPVYLAAVLEY CCCCHHHHHHHHHHH	6.92	26239621
58	Phosphorylation	YLAAVLEYLTAEILE HHHHHHHHHHHHHHH	12.75	26239621
96	Ubiquitination	RNDEELNKLLGGVTI CCHHHHHHHHCCEEE	58.68	-
102	Phosphorylation	NKLLGGVTIAQGGVL HHHHCCEEEECCCCC	17.55	27180971
119	Ubiquitination	IQAVLLPKKSSATVG EEEEEECCCCCCCCC	66.32	22790023
119	Acetylation	IQAVLLPKKSSATVG EEEEEECCCCCCCCC	66.32	23806337
120	Ubiquitination	QAVLLPKKSSATVGP EEEEECCCCCCCCCC	47.94	22790023
121	Phosphorylation	AVLLPKKSSATVGPK EEEECCCCCCCCCCC	31.19	27149854
122	Phosphorylation	VLLPKKSSATVGPKA EEECCCCCCCCCCCC	36.52	26824392
124	Phosphorylation	LPKKSSATVGPKAPA ECCCCCCCCCCCCCC	28.13	26239621
128	Malonylation	SSATVGPKAPAVGKK CCCCCCCCCCCCCHH	62.16	26320211
128	Acetylation	SSATVGPKAPAVGKK CCCCCCCCCCCCCHH	62.16	23806337
128	Ubiquitination	SSATVGPKAPAVGKK CCCCCCCCCCCCCHH	62.16	27667366
134	Acetylation	PKAPAVGKKASQASQ CCCCCCCHHHHHHHH	38.27	23806337
134	Sumoylation	PKAPAVGKKASQASQ CCCCCCCHHHHHHHH	38.27	28289178
137	Phosphorylation	PAVGKKASQASQEY- CCCCHHHHHHHHCC-	34.85	27087446
140	Phosphorylation	GKKASQASQEY---- CHHHHHHHHCC----	18.86	27087446
143	Phosphorylation	ASQASQEY------- HHHHHHCC-------	19.06	24899341

Upstream regulatory proteins (kinases for phosphorylation sites, E3 ubiquitin ligases of ubiquitination sites, ...)

Modified Location	Modified Residue	Modification	Type of Upstream Proteins	Gene Name of Upstream Proteins	UniProt AC of Upstream Proteins	Sources
139	S	Phosphorylation	Kinase	ATM	Q62388	PSP
139	S	Phosphorylation	Kinase	MAPK8	Q91Y86	GPS
139	S	Phosphorylation	Kinase	MAPK9	Q9WTU6	GPS
140	S	Phosphorylation	Kinase	ATM	Q62388	Uniprot
140	S	Phosphorylation	Kinase	ATR	Q9JKK8	Uniprot
140	S	Phosphorylation	Kinase	PRKDC	P97313	Uniprot
143	Y	Phosphorylation	Kinase	WSTF	Q9Z277	Uniprot
143	Y	Phosphorylation	Kinase	BAZ1B	-	GPS

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Function	Reference
14	K	ubiquitylation	Ubiquitination at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) in response to DNA damage is initiated by RNF168 that mediates monoubiquitination at these 2 sites, and 'Lys-63'-linked ubiquitin are then conjugated to monoubiquitin; RNF8 is able to extend 'Lys-63'-linked ubiquitin chains in vitro.	20488183
16	K	ubiquitylation	Ubiquitination at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) in response to DNA damage is initiated by RNF168 that mediates monoubiquitination at these 2 sites, and 'Lys-63'-linked ubiquitin are then conjugated to monoubiquitin; RNF8 is able to extend 'Lys-63'-linked ubiquitin chains in vitro.	20488183
37	K	Acetylation	Acetylation at Lys-37 increases in S and G2 phases.	20488183
63	K	ubiquitylation	Following DNA double-strand breaks (DSBs), it is ubiquitinated through 'Lys-63' linkage of ubiquitin moieties by the E2 ligase UBE2N and the E3 ligases RNF8 and RNF168, leading to the recruitment of repair proteins to sites of DNA damage.	-
120	K	ubiquitylation	Monoubiquitination of Lys-120 (H2AXK119ub) by RING1 and RNF2/RING2 complex gives a specific tag for epigenetic transcriptional repression.	20488183
140	S	Phosphorylation	Dephosphorylation of Ser-140 by PP2A is required for DNA DSB repair.	9488723
140	S	Phosphorylation	During immunoglobulin class switch recombination in lymphocytes, Ser-140 phosphorylation (H2AX139ph) at sites of DNA-recombination requires the activation-induced cytidine deaminase AICDA.	9488723
140	S	Phosphorylation	In contrast, dephosphorylation of Tyr-143 by EYA proteins (EYA1, EYA2, EYA3 or EYA4) favors the recruitment of MDC1-containing DNA repair complexes to the tail of phosphorylated Ser-140 (H2AX139ph).	9488723
140	S	Phosphorylation	In meiosis, Ser-140 phosphorylation (H2AX139ph) first occurs at synaptonemal complexes during leptotene and is an ATM-dependent response to the formation of programmed DSBs by SPO11.	9488723
140	S	Phosphorylation	Phosphorylated on Ser-140 (to form gamma-H2AX or H2AX139ph) in response to DNA double strand breaks (DSBs) generated by exogenous genotoxic agents, by stalled replication forks, by meiotic recombination events and during immunoglobulin class switching in lymphocytes.	9488723
140	S	Phosphorylation	Phosphorylation of Ser-140 (H2AX139ph) in response to ionizing radiation is mediated by both ATM and PRKDC while defects in DNA replication induce Ser-140 phosphorylation (H2AX139ph) subsequent to activation of ATR and PRKDC.	9488723
140	S	Phosphorylation	Ser-140 phosphorylation (H2AX139ph) may also be required for transcriptional repression of unsynapsed chromatin and meiotic sex chromosome inactivation (MSCI), whereby the X and Y chromosomes condense in pachytene to form the heterochromatic XY-body.	9488723
140	S	Phosphorylation	Ser-140 phosphorylation (H2AX139ph) subsequently occurs at unsynapsed regions of both autosomes and the XY bivalent during zygotene and is ATR- and BRCA1-dependent.	9488723

Disease-associated PTM Sites based on SAP

* Distance = the distance between SAP position and PTM sites.

Oops, there are no SNP-PTM records of H2AX_MOUSE !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
NBN_HUMAN	NBN	physical	12792649
TP53B_HUMAN	TP53BP1	physical	12792649
FACD2_MOUSE	Fancd2	physical	17304220
TP53B_MOUSE	Trp53bp1	physical	12792649
NBN_MOUSE	Nbn	physical	12792649
MDC1_MOUSE	Mdc1	physical	25703348
PSIP1_MOUSE	Psip1	physical	25703348
SRRM2_MOUSE	Srrm2	physical	25703348
HSP72_MOUSE	Hspa2	physical	25703348
SP16H_MOUSE	Supt16	physical	25703348

Drug and Disease Associations

• Kegg Drug
• DrugBank
• There are no disease associations of PTM sites.

Related Literatures of Post-Translational Modification

Acetylation

"Quantitative determination of histone modification. H2A acetylationand phosphorylation.";
Pantazis P., Bonner W.M.;
J. Biol. Chem. 256:4669-4675(1981).
Cited for: PHOSPHORYLATION AT SER-2, AND ACETYLATION AT SER-2.
PubMed: 7217105

"Acetylation of H2AX on lysine 36 plays a key role in the DNA double-strand break repair pathway.";
Jiang X., Xu Y., Price B.D.;
FEBS Lett. 584:2926-2930(2010).
Cited for: ACETYLATION AT LYS-37, AND MUTAGENESIS OF LYS-6; LYS-10; LYS-14;LYS-16; LYS-37; 119-LYS-LYS-120 AND SER-140.
PubMed: 20488183

Phosphorylation

"Silencing of unsynapsed meiotic chromosomes in the mouse.";
Turner J.M.A., Mahadevaiah S.K., Fernandez-Capetillo O.,Nussenzweig A., Xu X., Deng C.-X., Burgoyne P.S.;
Nat. Genet. 37:41-47(2005).
Cited for: FUNCTION, AND PHOSPHORYLATION AT SER-140.
PubMed: 15580272

"ATM and DNA-PK function redundantly to phosphorylate H2AX afterexposure to ionizing radiation.";
Stiff T., O'Driscoll M., Rief N., Iwabuchi K., Loebrich M.,Jeggo P.A.;
Cancer Res. 64:2390-2396(2004).
Cited for: SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT SER-140.
PubMed: 15059890

"H2AX regulates meiotic telomere clustering.";
Fernandez-Capetillo O., Liebe B., Scherthan H., Nussenzweig A.;
J. Cell Biol. 163:15-20(2003).
Cited for: FUNCTION, AND PHOSPHORYLATION AT SER-140.
PubMed: 14530383

"Phosphorylation of histone H2AX and activation of Mre11, Rad50, andNbs1 in response to replication-dependent DNA double-strand breaksinduced by mammalian DNA topoisomerase I cleavage complexes.";
Furuta T., Takemura H., Liao Z.-Y., Aune G.J., Redon C.,Sedelnikova O.A., Pilch D.R., Rogakou E.P., Celeste A., Chen H.T.,Nussenzweig A., Aladjem M.I., Bonner W.M., Pommier Y.;
J. Biol. Chem. 278:20303-20312(2003).
Cited for: FUNCTION, AND PHOSPHORYLATION AT SER-140.
PubMed: 12660252

"DNA damage-induced G2-M checkpoint activation by histone H2AX and53BP1.";
Fernandez-Capetillo O., Chen H.-T., Celeste A., Ward I.,Romanienko P.J., Morales J.C., Naka K., Xia Z., Camerini-Otero R.D.,Motoyama N., Carpenter P.B., Bonner W.M., Chen J., Nussenzweig A.;
Nat. Cell Biol. 4:993-997(2002).
Cited for: FUNCTION, SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT SER-140.
PubMed: 12447390

"Recombinational DNA double-strand breaks in mice precede synapsis.";
Mahadevaiah S.K., Turner J.M.A., Baudat F., Rogakou E.P., de Boer P.,Blanco-Rodriguez J., Jasin M., Keeney S., Bonner W.M., Burgoyne P.S.;
Nat. Genet. 27:271-276(2001).
Cited for: SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-140, AND TISSUESPECIFICITY.
PubMed: 11242108

"AID is required to initiate Nbs1/gamma-H2AX focus formation andmutations at sites of class switching.";
Petersen S., Casellas R., Reina-San-Martin B., Chen H.T.,Difilippantonio M.J., Wilson P.C., Hanitsch L., Celeste A.,Muramatsu M., Pilch D.R., Redon C., Ried T., Bonner W.M., Honjo T.,Nussenzweig M.C., Nussenzweig A.;
Nature 414:660-665(2001).
Cited for: FUNCTION, SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT SER-140.
PubMed: 11740565

"ATM phosphorylates histone H2AX in response to DNA double-strandbreaks.";
Burma S., Chen B.P., Murphy M., Kurimasa A., Chen D.J.;
J. Biol. Chem. 276:42462-42467(2001).
Cited for: SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT SER-140.
PubMed: 11571274

"DNA double-stranded breaks induce histone H2AX phosphorylation onserine 139.";
Rogakou E.P., Pilch D.R., Orr A.H., Ivanova V.S., Bonner W.M.;
J. Biol. Chem. 273:5858-5868(1998).
Cited for: PHOSPHORYLATION AT SER-140.
PubMed: 9488723

"Quantitative determination of histone modification. H2A acetylationand phosphorylation.";
Pantazis P., Bonner W.M.;
J. Biol. Chem. 256:4669-4675(1981).
Cited for: PHOSPHORYLATION AT SER-2, AND ACETYLATION AT SER-2.
PubMed: 7217105

"WSTF regulates the H2A.X DNA damage response via a novel tyrosinekinase activity.";
Xiao A., Li H., Shechter D., Ahn S.H., Fabrizio L.A.,Erdjument-Bromage H., Ishibe-Murakami S., Wang B., Tempst P.,Hofmann K., Patel D.J., Elledge S.J., Allis C.D.;
Nature 457:57-62(2009).
Cited for: PHOSPHORYLATION AT TYR-143.
PubMed: 19092802