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 [, ].
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 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 [].
Claspin is an essential protein for the ATR-Chk1-dependent activation ofthe DNA replication checkpoint response in Xenopus and human cells [, ]. DNA damage induces the formation of a complex between Claspin and BRCA1, a second regulator of Chk1 activation. It is thought that ATR regulates Claspin phosphorylation in response to DNA damage and replication stress, resulting in recruitment and phosphorylation of BRCA1. BRCA1 and Claspin then function to activate Chk1 [].This entry represents both claspin and claspin homologues found mainly in Drosophila.
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 [].
This entry represents Rad9, Rad1, Hus1-interacting nuclear orphan protein 1 (RHINO or RHNO1), which plays a role in DNA damage response (DDR) signalling upon genotoxic stresses such as ionizing radiation (IR) during the S phase []. RHNO1 is recruited to sites of DNA damage through interaction with the Rad9-Rad1-Hus1 (9-1-1) complex and ATR activator TopBP1. It plays a role in ATR-mediated activation of Chk1 driven by TopBP1 and 9-1-1 []. It is involved in mammary carcinogenesis [].
The function of the ATR-ATRIP (ATR-interacting protein) protein kinase complex is crucial for the cellular response to replication stress and DNA damage. ATRIP is a regulatory partner of ATR. The binding of ATRIP to replication protein A-coated ssDNA at sites of DNA damage drives ATR activation and enables the ATR-ATRIP complex to stimulate phosphorylation of substrates, such as Rad17 or Chk1, and the initiation of checkpoint signalling []. ATRIP deacetylation by SIRT2 promotes ATR-ATRIP bindingto RPA-ssDNA [].
This entry represents the budding yeast Ddc1, which is homologous to the fission yeast and human Rad9.DNA-damage checkpoint protein 1 (Ddc1) forms a checkpoint clamp complex with Mec3 and Rad17 [, ]. This complex plays a role in the surveillance system that permits DNA-repair pathways to restore the integrity of DNA in advance of DNA synthesis or separation of replicated chromosomes, thereby ensuring that new phases are not entered if DNA is damaged []. Ddc1 can activate Mec1 (the principal checkpoint protein kinase, human ATR homologue) in G1 phase. In G2 phase, Ddc1 can either activate Mec1 directly or recruit Dpb11 (ortholog of human TopBP1) and subsequently activate Mec1 []. Ddc1 does not have the DNA exonuclease function [].
Checkpoint kinase 1 (Chk1) is a serine/threonine kinase implicated in many major checkpoints of the cell cycle, providing a link between upstream sensors and the cell cycle engine. It plays an important role in DNA damage response and maintaining genomic stability [, , ]. Chk1 acts as an effector of the sensor kinase, ATR (ATM and Rad3-related), a member of the PI3K family, which is activated upon DNA replication stress []. Chk1 delays mitotic entry in response to replication blocks by inhibiting cyclin dependent kinase (Cdk) activity. In addition, Chk1 contributes to the function of centrosome and spindle-based checkpoints, inhibits firing of origins of DNA replication (Ori), and represses transcription of cell cycle proteins including cyclin B and Cdk1 [, ].
ATP-binding cassette transporters (ABC) are multipass transmembrane proteins that use the energy of ATP hydrolysis to transport substrates across membrane bilayers. Members of ABC transporter subfamily A are full-length transporters [], which consist of a single long polypeptide chain organised into two tandemly arranged halves. Each half contains a membrane-spanning domain (MSD) followed by a cytoplasmic nucleotide binding domain (NBD) []. Several members of this group have been shown to mediate the transport of a variety of physiologic lipid compounds, such as sterols, phospholipids and bile acids [, ].ABCA7 plays a role in clearance of apoptotic cells by affecting their phagocytosis []. In the human visual cycle, ABCA4 acts as an inward-directed retinoid flipase, retinoid substrates imported by ABCA4 from the extracellular or intradiscal (rod) membrane surfaces to the cytoplasmic membrane surface are all-trans-retinaldehyde (ATR) and N-retinyl-phosphatidyl-ethanolamine (NR-PE). Once transported to the cytoplasmic surface, ATR is reduced to vitamin A by trans-retinol dehydrogenase (tRDH) and then transferred to the retinal pigment epithelium (RPE) where it is converted to 11-cis-retinal. ABCA4 may also play a role in photoresponse, removing ATR/NR-PE from the extracellular photoreceptor surfaces during bleach recovery []. It has been suggested that ABCA9 plays a role in monocyte differentiation and lipid homeostasis [].
This entry represents the DNA damage checkpoint protein Rad9 and its homologue in budding yeast, Ddc1. Rad9 forms a complex with Hus1 and Rad1 (called 9-1-1 complex). Ddc1 forms a similar complex with Mec1 and Rad17. Structurally, the 9-1-1 / Ddc1-Mec3-Rad17 complex is similar to the PCNA complex, which forms trimeric ring-shaped clamps. The 9-1-1 / Ddc1-Mec3-Rad17 complex plays a role in checkpoint activation that permits DNA-repair pathways to prevent cell cycle progression in response to DNA damage and replication stress [, ].In humans, 9-1-1 binds to TopBP1 and activates the ATR-Chk1 checkpoint pathway []. Besides its function in the 9-1-1 complex, Rad9 can also act as a transcriptional factor and participate in immunoglobulin class switch recombination []. It also shows 3'-5' exonuclease activity []. Aberrant Rad9 expression has been associated with prostate, breast, lung, skin, thyroid, and gastric cancers [].In budding yeast, Ddc1 can activate Mec1 (the principal checkpoint protein kinase, human ATR homologue) in G1 phase. In G2 phase, Ddc1 can either activate Mec1 directly or recruit Dpb11 (the orthologue of human TopBP1) and subsequently activate Mec1 []. Ddc1 does not have DNA exonuclease function [].It is worth noting that the Rad9 proteins referred to in this entry are the mammalian and fission yeast homologues of budding yeast Ddc1. Members of this family do not share the sequence homology another DNA damage-dependent checkpoint protein from budding yeast, confusingly also called Rad9.
