241 human active and 13 inactive phosphatases in total;
194 phosphatases have substrate data;
336 protein substrates;
83 non-protein substrates;
1215 dephosphorylation interactions;
299 KEGG pathways;
876 Reactome pathways;
last scientific update: 11 Mar, 2019
last maintenance update: 01 Sep, 2023
Cytoplasm Nucleus Note=Localizes at sites of DNAdamage at double-strand breaks (DSBs)
Function (UniProt annotation)
Functions both as protein phosphatase and astranscriptional coactivator for SIX1, and probably also for SIX2,SIX4 and SIX5 (By similarity) Tyrosine phosphatase thatdephosphorylates 'Tyr-142' of histone H2AX (H2AXY142ph) andpromotes efficient DNA repair via the recruitment of DNA repaircomplexes containing MDC1 'Tyr-142' phosphorylation of histoneH2AX plays a central role in DNA repair and acts as a mark thatdistinguishes between apoptotic and repair responses to genotoxicstress (PubMed:19234442) Its function as histone phosphatase maycontribute to its function in transcription regulation duringorganogenesis (By similarity) Has also phosphatase activity withproteins phosphorylated on Ser and Thr residues (in vitro) (Bysimilarity) Required for normal embryonic development of thecraniofacial and trunk skeleton, kidneys and ears (By similarity)Together with SIX1, it plays an important role in hypaxial muscledevelopment; in this it is functionally redundant with EYA2 (Bysimilarity)
In tumor cells, genes encoding transcription factors (TFs) are often amplified, deleted, rearranged via chromosomal translocation and inversion, or subjected to point mutations that result in a gain- or loss-of- function. In hematopoietic cancers and solid tumors, the translocations and inversions increase or deregulate transcription of the oncogene. Recurrent chromosome translocations generate novel fusion oncoproteins, which are common in myeloid cancers and soft-tissue sarcomas. The fusion proteins have aberrant transcriptional function compared to their wild-type counterparts. These fusion transcription factors alter expression of target genes, and thereby result in a variety of altered cellular properties that contribute to the tumourigenic process.
Activated ATM phosphorylates a number of proteins involved in the DNA damage checkpoint and DNA repair (Thompson and Schild 2002, Ciccia and Elledge 2010), thereby triggering and coordinating accumulation of DNA DSB repair proteins in nuclear foci known as ionizing radiation-induced foci (IRIF). While IRIFs include chromatin regions kilobases away from the actual DSB site, this Reactome pathway represents simplified foci and events that happen proximal to the DNA DSB ends. In general, proteins localizing to the nuclear foci in response to ATM signaling are cooperatively retained at the DNA DSB site, forming a positive feedback loop and amplifying DNA damage response (Soutoglou and Misteli 2008).
Activated ATM phosphorylates the NBN (NBS1) subunit of the MRN complex (MRE11A:RAD50:NBN) (Gatei et al. 2000), as well as the nucleosome histone H2AFX (H2AX) on serine residue S139, producing gamma-H2AFX (gamma-H2AX) containing nucleosomes (Rogakou et al. 1998, Burma et al. 2001). H2AFX is phosphorylated on tyrosine 142 (Y142) under basal conditions (Xiao et al. 2009). After ATM-mediated phosphorylation of H2AFX on S139, tyrosine Y142 has to be dephosphorylated by EYA family phosphatases in order for the DNA repair to proceed and to avoid apoptosis induced by DNA DSBs (Cook et al. 2009). Gamma-H2AFX recruits MDC1 to DNA DSBs (Stucki et al. 2005). After ATM phosphorylates MDC1 (Liu et al. 2012), the MRN complex, gamma-H2AFX nucleosomes, and MDC1 serve as a core of the nuclear focus and a platform for the recruitment of other proteins involved in DNA damage signaling and repair (Lukas et al. 2004, Soutoglou and Misteli 2008).
RNF8 ubiquitin ligase binds phosphorylated MDC1 (Kolas et al. 2007) and, in cooperation with HERC2 and RNF168 (Bekker-Jensen et al. 2010, Campbell et al. 2012), ubiquitinates H2AFX (Mailand et al. 2007, Huen et al. 2007, Stewart et al. 2009, Doil et al. 2009) and histone demethylases KDM4A and KDM4B (Mallette et al. 2012).
Ubiquitinated gamma-H2AFX recruits UIMC1 (RAP80), promoting the assembly of the BRCA1-A complex at DNA DSBs. The BRCA1-A complex consists of RAP80, FAM175A (Abraxas), BRCA1:BARD1 heterodimer, BRCC3 (BRCC36), BRE (BRCC45) and BABAM1 (MERIT40, NBA1) (Wang et al. 2007, Wang and Elledge 2007)
Ubiquitin mediated degradation of KDM4A and KDM4B allows TP53BP1 (53BP1) to associate with histone H4 dimethylated on lysine K21 (H4K20Me2 mark) by WHSC1 at DNA DSB sites (Pei et al. 2011).
Once recruited to DNA DSBs, both BRCA1:BARD1 heterodimers and TP53BP1 are phosphorylated by ATM (Cortez et al. 1999, Gatei et al. 2000, Kim et al. 2006, Jowsey et al. 2007), which triggers recruitment and activation of CHEK2 (Chk2, Cds1) (Wang et al. 2002, Wilson and Stern 2008, Melchionna et al. 2000).
Depending on the cell cycle stage, BRCA1 and TP53BP1 competitively promote either homology directed repair (HDR) or nonhomologous end joining (NHEJ) of DNA DSBs. HDR through homologous recombination repair (HRR) or single strand annealing (SSA) is promoted by BRCA1 in association with RBBP8 (CtIP), while NHEJ is promoted by TP53BP1 in association with RIF1 (Escribano-Diaz et al. 2013)