BRAT1 binds to ATM and BRCA1 and is involved in DNA damage-induced ATM activation []. It is also involved in cell proliferation and mitochondrial functions []. Mutations of the BRAT1 gene have been linked to epileptic encephalopathy [, ].
This entry represents ATM (Ataxia Telangiectasia Mutated) from plants, including AtATM from Arabidopsis. AtATM is an Arabidopsis homologue of the human ATM gene. ATM is an essential checkpoint kinase that signals DNA double-strand breaks in eukaryotes. AtATM plays a important role in the response to both stress-induced and developmentally programmed DNA damage [, ].
Human MAP9 is involved in organisation of the mitotic spindle []. Besides being required for mitosis progression and cytokinesis, it may stabilise interphase microtubules []. Upon DNA damage, it is phosphorylated probably by ATM or ATR [].
Members of this vertebrate family of proteins are targets for phosphorylation by CDK1 and casein kinase [, ]. They are also phosphorylated upon DNA damage, probably by ATM or ATR [].
Centrosomal protein of 95kDa is localised to the centrosome and the spindle pole []. Its function is not clear. It is phosphorylated upon DNA damage, probably by ATM or ATR [, ].
ATM acts as a DNA damage sensor upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA) [, ]. It regulate DNA damage response mechanism through recognising the substrate consensus sequence [ST]-Q and phosphorylates 'Ser-139' of histone variant H2AX/H2AFX at double strand breaks (DSBs) []. On DNA damage, autophosphorylation dissociates ATM into monomers rendering them catalytically active [, ]. It can phosphorylate DYRK2, CHEK2, p53/TP53, FANCD2, NFKBIA, BRCA1, CTIP, nibrin (NBN), TERF1, RAD9 and DCLRE1C [, , , , ]. ATM is also required for telomere elongation []. ATM also plays a role in pre-B cell allelic exclusion, a process leading to expression of a single immunoglobulin heavy chain allele to enforce clonality and monospecific recognition by the B-cell antigen receptor (BCR) expressed on individual B-lymphocytes []. It isalso involved in signal transduction and cell cycle control and may function as a tumour suppressor [].This entry represents the catalytic domain found in serine-protein kinase ATM.
Centrosomal protein of 170kDa (Cep170) plays a role in microtubule organisation []. Human Cep170 is constantly expressed throughout the cell cycle but phosphorylated during mitosis. Cep170 is a substrate of Polo-like kinase 1 (Plk1) []. It is associated with the mature mother centriole. Upon DNA damage, it is phosphorylated probably by ATM or ATR [, , ].
This is a domain of unknown function with homology to the CH domain. This domain can be found in CEP95CEP95 is localised to the centrosome and the spindle pole []. Its function is not clear. It is phosphorylated upon DNA damage, probably by ATM or ATR [, ].
This entry represents receptor-interacting serine/threonine-protein kinase 2 (RIP2), which functions in the phosphorylation () of its protein target. This enzyme activates pro-caspase-1 and pro-caspase-8, and it thought to potentiate CASP8-mediated apoptosis []. It also activates NF-kappa-B. RIP2 undergoes autophosphorylation; it is phosphorylated upon DNA damage, probably by ATM or ATR.
This family consists of serine/threonine protein kinases, including human ATM (Ataxia-Telangiectasia Mutated) and fungal Tel1.ATM acts as a DNA damage sensor upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA) [, ]. It regulate DNA damage response mechanism through recognizing the substrate consensus sequence [ST]-Q and phosphorylates 'Ser-139' of histone variant H2AX/H2AFX at double strand breaks (DSBs) []. On DNA damage, autophosphorylation dissociates ATM into monomers rendering them catalytically active [, ]. It can phosphorylate DYRK2, CHEK2, p53/TP53, FANCD2, NFKBIA, BRCA1, CTIP, nibrin (NBN), TERF1, RAD9 and DCLRE1C [, , , , ]. ATM is also required for telomere elongation []. ATM also plays a role in pre-B cell allelic exclusion, a process leading to expression of a single immunoglobulin heavy chain allele to enforce clonality and monospecific recognition by the B-cell antigen receptor (BCR) expressed on individual B-lymphocytes []. It is also involved in signal transduction and cell cycle control and may function as a tumour suppressor [].
In Saccharomyces cerevisiae Rif1 interacts with Rif2 and Rap1 to regulate telomere length and establish telomeric silencing []. Despite the protein sequence similarity with yeast Rif1, human Rif1 does not bind to Rap1 and does not accumulate at functional telomeres. Human Rif1 is required for checkpoint mediated arrest of cell cycle progression in response to DNA damage during S-phase (the intra-S-phase checkpoint) and is regulated by ATM and 53BP1 [].
This entry represents the FAM178 family, whose members are metazoan proteins and include FAM178A and FAM178B. The human FAM178A protein has been shown to be widely expressed []and is phosphorylated upon DNA damage, probably by ATM (ataxia telangiectasia mutated) or ATR (ATM and Rad3-related) [, ].FAM178A, also known as SLF2 (SMC5-SMC6 complex localization factor 2), forms a complex with RAD18 and SLF1, and together they define a pathway that suppresses genome instability by recruiting the SMC5/6 cohesion complex to DNA lesions [, ].
SIN3-HDAC complex-associated factor (also known as FAM60A) is found in eukaryotes. It has been shown to be a subunit of the Sin3 deacetylase complex (Sin3/HDAC), important for the repression of genes involved in the TGF-beta signaling pathway [, ]. Human FAM60A protein has been shown to be up-regulated in squamous cell carcinoma (SCC), adenocarcinoma (AC), colon, ovary, rectum and stomach tumors. Human FAM60A is phosphorylated upon DNA damage, probably by ATM or ATR [].
RAD51-associated protein 1 may participate in a common DNA damage response pathway associated with the activation of homologous recombination and double-strand break repair []. It functionally cooperates with PALB2 in promoting of D-loop formation by RAD51 [, ]. It binds to single and double stranded DNA, and is capable of aggregating DNA []. It also binds RNA []. It is phosphorylated upon DNA damage, probably by ATM or ATR [, , ].
This entry represents ubinuclein-2 (UBN2). It contains a conserved HIRA-binding domain, which directly interacts with the N-terminal WD repeats of HIRA []. UBN2 and UBN1 are believed to be the orthologs of Hpc2p, a subunit of the HIR complex (a nucleosome assembly complex involved in regulation of histone gene transcription) in budding yeast []. It is phosphorylated upon DNA damage, probably by ATM or ATR [].
PLK3 (polo-like kinase 3) is a serine/threonine-protein kinase involved in cell cycle regulation, response to stress and Golgi disassembly [, , ]. It regulates angiogenesis and responses to DNA damage []. Activated PLK3 mediates Chk2 phosphorylation by ATM and the resulting checkpoint activation []. PLK3 phosphorylates DNA polymerase delta and may be involved in DNA repair. It also inhibits Cdc25c, thereby regulating the onset of mitosis [, ].
SMG-1 plays a critical role in the mRNA surveillance mechanism known as non-sense mediated mRNA decay (NMD). NMD protects the cells from the accumulation of aberrant mRNAs with premature termination codons (PTCs) generated by genome mutations and by errors during transcription and splicing. SMG-1 phosphorylates Upf1, another central component of NMD, at the C terminus upon recognition of PTCs. The phosphorylation/dephosphorylation cycle of Upf1 is essential for promoting NMD []. In addition to its catalytic domain, SMG-1 contains a FATC (FRAP, ATM and TRRAP, C-terminal) domain at the C terminus. SMG-1 is a member of the phosphoinositide 3-kinase-related protein kinase (PIKK) subfamily. PIKKs have intrinsic serine/threonine kinase activity and are distinguished from other PKs by their unique catalytic domain, similar to that of lipid PI3K, and their large molecular weight (240-470kDa) []. This entry represents the SMG-1 catalytic domain.
PLK3 (polo-like kinase 3) is a serine/threonine-protein kinase involved in cell cycle regulation, response to stress and Golgi disassembly [, , ]. It regulates angiogenesis and responses to DNA damage []. Activated PLK3 mediates Chk2 phosphorylation by ATM and the resulting checkpoint activation []. PLK3 phosphorylates DNA polymerase delta and may be involved in DNA repair. It also inhibits Cdc25c, thereby regulating the onset of mitosis [, ].STKs (serine/threonine-protein kinases) catalyse the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PLKs (polo-like kinases) play important roles in cell cycle progression and in DNA damage responses. They regulate mitotic entry, mitotic exit, and cytokinesis. In general PLKs contain an N-terminal catalytic kinase domain and a C-terminal regulatory polo box domain (PBD), which is comprised by two bipartite polo-box motifs (or polo boxes) and is involved in protein interactions. There are five mammalian PLKs (PLK1-5) from distinct genes [, , ].
ATM is a large protein kinase, in humans, critical for responding to DNA double-strand breaks (DSBs). Tel1, the orthologue from budding yeast, also regulates responses to DSBs. Tel1 is important for maintaining viability and for phosphorylation of the DNA damage signal transducer kinase Rad53 (an orthologue of mammalian CHK2). In addition to functioning in the response to DSBs, numerous findings indicate that Tel1/ATM regulates telomeres. The overall domain structure of Tel1/ATM is shared by proteins of the phosphatidylinositol 3-kinase (PI3K)-related kinase (PIKK) family, but this family carries a unique and functionally important TAN sequence motif, near its N-terminal, LxxxKxxE/DRxxxL. which is conserved specifically in the Tel1/ATM subclass of the PIKKs. The TAN motif is essential for both telomere length maintenance and Tel1 action in response to DNA damage []. It is classified as an .
