Exposure to mutagenic agents results in DNA damage.
That DNA Damage must be rigorously dealt with in order to prevent the cell from propagating mutations that can result in genomic instability and malignant transformation. To address the constant threat of genotoxic stress, animal cells have evolved a DNA damage response that is governed by a complex and highly-branched signaling network. The components of this network function to sense DNA lesions and transduce cellular signals that activate transcriptional programs for the initiation of DNA repair, cell death, or cell cycle arrest.
There are three cell cycle checkpoint pathways that arrest or delay DNA synthesis when genetic damage is sensed. The G1, S, and G2 cell cycle checkpoints are primarily regulated by the ATM (ataxia telangiectasia, mutated) and ATR (ATM and Rad3-related) protein kinases. ATM and ATR are members of the PI-3 family of serine-threonine kinases and function as essential links between the sensors and effectors of the DNA damage response. The roles of ATM and ATR partially overlap and are cooperative; however they are also known to play distinct roles in protecting the cell from DNA damage. ATM is mostly responsible for sending signals from DSBs (double-strand breaks) induced by ionizing radiation while the closely related ATR responds to UV damage or stalled replication forks.
ATM and ATR are known to phosphorylate common as well as specific substrates to activate checkpoint signaling. The list of reported substrates of these kinases is sizable and continues to grow. The ever-expanding and elaborate downstream network of ATM and ATR signaling illustrates both the versatility and complexity of this pathway and presents many directions of research that will require further exploration for a complete understanding of the DNA damage response. Even more paths of research remain for understanding the upstream events that take place at the level of sensing DNA damage and grasping how this is linked to ATM and ATR activation.
Bethyl Laboratories portfolio of antibodies to proteins involved in ATM and ATR signaling, includes:
| 4EBP1 Eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) binds directly to eIF4E to inhibit complex assembly for translation initiation. 4EBP1 is part of a family of translation repressor proteins. 4EBP1 is directly phosphorylated by the mTORC1 complex during growth factor stimulation of cells. Phosphorylation of 4EBP1 causes its release from eIF4E to allow translation to proceed. 4EBP1 is also called eIF4E-binding protein, phosphorylated heat-and-acid-stable protein regulated by insulin 1, PHAS-I, EIF4EBP1, BP-1, and MGC4316. |
| 53BP1 53BP1 (p53 Binding Protein 1) is an early participant in the cellular response to DNA double-strand breaks. 53BP1 functions in a redundant role in phosphorylation of the downstream checkpoint effector proteins Brca1 and Chk2 but was required for the formation of Brca1 foci in a hierarchical branched pathway for the recruitment of repair and signaling proteins to sites of DNA damage. Alternate names for 53BP1 include Tumor protein p53 binding protein 1 and p202. |
| Artemis Artemis is also known as DNA cross-link repair 1C protein (DCLRE1C) and functions as both an endo- and exo-nuclease involved in V(D)J recombination and double-strand break (DSB) repair. In addition to repair of double stranded breaks during V(D)J recombination, Artemis may also be required for repair of ionizing radiation induced DSBs. Mutations in Artemis have been found to be a cause of severe combined immunodeficiency (SCID). Alternate names for Artemis include SNM1-like protein, A-SCID protein, hSNM1C, ASCID, SCIDA, SNM1C, FLJ11360, and FLJ36438. |
| ATF2 Activating transcription factor 2 (ATF2) is a leucine-zipper transcription factor that binds to the cAMP-responsive element (CRE). ATF2 is involved in regulating the expression of a variety of proteins that are important to oncogenesis. It is a substrate of the JNK/p38 and ATM/ATR protein kinases which regulate its transactivating activity in response to environmental signals. Alternate names for ATF2 include cAMP response element-binding protein CRE-BP1, HB16, CREB2, and CREBP1. |
| ATM Ataxia telangiectasia, mutated (ATM) is the gene responsible for the neurodegenerative disease ataxia telangiectasia (AT). AT is characterized by neurodegeneration, immune dysfunction, sensitivity to DNA damage, and cancer predisposition. ATM is a protein kinase central to the DNA damage response. In response to DNA double-strand breaks (DSBs), ATM initiates a signaling cascade that involves the phosphorylation of a multitude of substrates which include p53, BRCA1, p53 binding protein, CHK2, RAD9, RAD17, and MDM4. Alternate names for ATM include AT1, ATA, ATC, ATD, ATE, ATDC, TEL1, TELO1, MGC74674, Serine protein kinase ATM, human phosphatidylinositol 3 kinase homolog, AT protein, and DKFZp781A0353. |
| ATR ATR (ATM and Rad3 related) is closely related to ATM (Ataxia telangiectasia, mutated) and is a member of the phosphatidylinositol 3 kinase (PI-3) family that is an early sensor of DNA damage. ATR is a serine-threonine kinase that reacts to UV damage and interruptions in replication. ATR may be able to sense DNA damage through interaction with Rad17 and 1as well as components of nucleosome remodeling complexes. In response to DNA damage, ATR has been shown to phosphorylate a multitude of substrates which include BRCA1, p53, Chk2, Rad 17, and E2F transcription factor 1. ATR is also known as serine/threonine-protein kinase ATR, FRAP-related protein 1, FRP1, MEC1, SCKL, and SCKL1. |
| ATRIP ATRIP (ATR-interacting protein) forms a complex with the serine-threonine kinase ATR (ataxia-telangiectasia mutated rad-3 related) to function in the DNA damage response. Through its interaction with replication protein A (RPA), ATRIP aids the recruitment of ATR to regions of DNA damage. ATR-ATRIP interacts with and is regulated by Rad17 and the 9-1-1 complexes. Alternate designations of ATRIP include ATM and Rad3-related-interacting protein, and AGS1. |
| BID BID (BH3-interacting domain death agonist) can mediate both apoptotic and pro-survival signals in response to DNA damage. BID is phosphorylated by ATM in response to DNA damage and may play a role in the cell’s decision of whether to live or die based on the extent of damage. BID is also known as p22 BID, p15 BID, p13 BID, p11 BID, AI875481, AU022477, and 2700049M22Rik. |
| BRCA1 BRCA1 was identified as a gene with germline mutations that predisposes women to breast and ovarian cancer. The BRCA1 tumor suppressor is a large protein that has been demonstrated to interact with a multitude of proteins involved in the DNA damage response and cell cycle checkpoints to maintain genomic integrity. BRCA1 functions by regulating the activities of its interacting proteins which mediate processes such as gene transcription, gene repression, protein phosphorylation, and ubiquitination. BRCA1 is also known as breast cancer type 1 susceptibility protein, RING finger protein 53, RNF53, IRIS, PSCP, BRCAI, and BRCC1. |
| cAbl c-Abl is the human cellular homolog of a the v-Abl viral oncogene. v-Abl was originally discovered as a mouse cell-derived sequence in the genome of the Abelson murine leukemia virus (A-MuLV), a transforming retrovirus isolated by the laboratory of Dr. H.T. Abelson. c-Abl is a tyrosine kinase from the Src-family of tyrosine kinases that localizes to both the cytoplasm and nucleus. It bears an SH2 (src-homology 2) and SH3 (src-homology 3) domain responsible for mediating c-Abl protein-protein interactions. c-Abl is implicated to play a role in multiple cellular processes such as cell cycle checkpoint signaling, apoptosis, cell differentiation, cell adhesion, and transcriptional regulation. Chromosomal translocations involving the c-Abl gene are associated with human leukemias. Alternate names for c-Abl include proto-oncogene tyrosine-protein kinase ABL1, Abelson murine leukemia viral oncogene homolog 1, p150, ABL1, ABL, and JTK7. |
| CDC25C CDC25c (cell division cycle 25 homolog c) is a member of the Cdc25 family of phosphatases. CDC25c promotes cell cycle progression and M-phase entry by dephosphorylating CDC2/cyclin B and activating its kinase activity. CDC25c is phosphorylated and activated by multiple kinases including chk1, Cdc2/cyclin B, polo-like kinase 1, and JNK MAP kinases. The inactivation of CDC25c phosphatase activity is achieved through dephosphorylation by PP1 and PP2A phosphatases. Alternate names for CDC25c include M-phase inducer phosphatase 3, and dual specificity phosphatase Cdc25C. |
| Chk1 Chk1 functions as a checkpoint protein kinase that is critical to the regulation of the Cdc25a and Cdc25c phosphatases that promote S and G2/M phase progression, respectively. Chk1 kinase activity inhibits cell cycle progression in the presence of DNA damage by phosphorylating Cdc25a and Cdc25c and causing the degradation of Cdc25a and cytoplasmic sequestration of Cdc25c. Alternate designations for Chk1 include serine/threonine-protein kinase Chk1, and CHEK1. |
| Chk2 Chk2 functions as a checkpoint protein kinase in response to DNA damage to maintain genomic stability. The yeast homologs are Rad53 and Cds1. The two major upstream controllers of Chk2 are ATM and ATR which are part of the phosphatidylinositol 3-kinase family. When activated, Chk2 targets p53, BRCA1, Cdc25A and Cdc25C to cause cell cycle arrest. Chk2 is also known as serine/threonine-protein kinase CHK2, CHEK2, CDS1, LFS2, Rad53, HuCds1, and PP1425. |
| CtIP CtIP (CTBP interacting protein) was first identified as a protein that interacted with CTBP (C-terminus-binding protein of adenovirus E1A). CtIP has also been identified as a protein that interacts with the tumor suppressors pRb and BRCA1 and has been implicated as a tumor suppressor itself. Alternate names for CtIP include CTIP, RBBP8, and RIM. |
| E2F1 E2F1 is a member of the E2F family of transcription factors. E2F is an activating member that binds DNA at the E2 recognition site in the promoters of genes involved in cell cycle regulation or DNA replication. E2F1 is regulated through its interaction with the pRb tumor suppressor. Alternate names for E2F1 include transcription factor E2F1, E2F-1, retinoblastoma-binding protein 3, RBBP-3, PRB-binding protein E2F1, PBR3, retinoblastoma-associated protein 1, RBAP-1, and RBP3. |
| FUS FUS has been identified as a frequent translocation fusion partner of various transcription factors. FUS fusion genes have been shown to be associated with multiple tumor types which include liposarcoma, leukemia, histocytoma, and sarcoma. FUS is a multifunctional RNA-binding protein that associates with the nuclear matrix and Cajal bodies and appears to play a role in splicesome assembly, pre-mRNA splicing, DNA repair, transcriptional regulation and homologous recombination. Alternate names for FUS include RNA-binding protein FUS, oncogene FUS, oncogene TLS, translocated in liposarcomas, TLS, 75 kDa DNA-pairing protein, POMp75, CHOP, FUS-CHOP, TLS/CHOP, and hnRNP-P2. |
| gamma-H2AX H2AX H2AX is a member of the histone H2A family. The four core histones involved in the formation of the nucleosome structure of compacted chromatin are H2A, H2B, H3, and H4. H2AX may function to facilitate DNA repair, and recent studies have shown that H2AX is required for the maintenance of genomic stability. Gamma H2AX is the phosphorylated form of H2AX that results in response to DNA damage. Alternate names for H2AX include histone H2A.x, and H2a/x. |
| HdmX/MDM4 HdmX/MDM4 is a RING-finger domain containing protein that interacts with p53. HdmX/MDM4 may influence p53 stability through an interaction with the structurally similar MDM2, an ubiquitin-ligase that targets p53 for proteasomal degradation. HdmX/MDM4 may influence p53 by directly attenuating p53 transcriptional activity. Alternate names for HdmX/MDM4 include p53-binding protein mdm4, mdm2-like p53-binding protein, double minute 4 protein, MDMX, MRP1, MGC132766, and DKFZp781B1423. |
| MCM3 The MCM (Mini-Chromosome Maintenance) complex is a key component of the pre-replication complex involved in replication licensing which restricts DNA replication to only once per cell cycle. The MCM complex is a heterohexamer of MCM2, MCM3, MCM4, MCM5, MCM6, and MCM7. MCM3 has been shown to interact with MCM5, CDC46, and the acetyltransferase MCM3AP. Alternate names for MCM3 include DNA replication licensing factor MCM3, DNA polymerase alpha holoenzyme-associated protein P1, RLF subunit beta, P102, P1-MCM3, HCC5, RLFB, and MGC1157. |
| MDC1 MDC1 is required for the S- and G2/M-checkpoint-mediated cell cycle arrest in response to DNA damage. MDC1 interacts with H2AX near sites of DNA double-strand breaks and recruits ATM kinase to foci of DNA damage. MDC1 also appears to regulate the function of other proteins involved in the DNA damage checkpoint such as BRCA1 and Chk2. Alternate names for MDC1 include mediator of DNA damage checkpoint protein 1, nuclear factor with BRCT domains 1, KIAA0170, NFBD1, and DKFZp781A0122. |
| Mre11 Mre11 is a component of the MRN complex and plays a role in telomere maintenance and double-strand break (DSB) repair. Mre11 associates with rad50 in the MRN complex. Mre11 possesses 3’– 5’ exonuclease activity that is involved in creating DNA termini in DSB suitable for priming DNA synthesis and ligation. Alternate names for Mre11 include double-strand break repair protein MER11A, MRE11 homolog 1, MRE11 meiotic recombination 11 homolog A, MRE11A, HNGS1, ATLD, and MRE11B. |
| NBS1 Mutations in NBS1 (Nijmegen Breakage Syndrome 1), also known as nibrin, are associated with the autosomal recessive syndrome, Nijmegen breakage syndrome, characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. At the cellular level, NBS1 is part of the MRE11/RAD50 double-strand break repair complex that is critical to the DNA damage response, DNA recombination, telomere integrity, and cell cycle checkpoint control. Alternate names for NBS1 include cell cycle regulatory protein p95, NBS, NBN, ATV, AT-V1, AT-V2, FLJ10155, and MGC87362. |
| p53 p53 is a tumor suppressor protein that is mutated or inactivated in over 50% of human cancers. Loss of function defects in p53 are the cause of the autosomal dominant familial cancer syndrome, Li-Fraumeni syndrome (LFS) that is characterized by the development of a diverse set of malignancies at very early ages. At the cellular level p53 is involved in the negative regulation of cell the cycle via its transactivational control of genes required for cell cycle progression. Depending on the physiological circumstance, p53 can promote growth arrest or apoptosis. Alternate names for p53 include cellular tumor antigen p53, tumor suppressor p53, phosphoprotein p53, antigen NY-CO-13, TP53, TRP53, and Li-Fraumeni syndrome. |
| PP2A PP2A is a major serine/threonine phosphatase that is implicated in the negative control of cell cycle progression. PP2A encodes the beta isoform of the catalytic subunit (PP2CB). Chk2 has been shown to be negatively regulated and dephosphorylated by PP2A. Several proteins have been shown to associate with PP2A and regulate its activity such as eRF1, Hox11, CK2, and Igbp1/alpha4. Rapamycin has been shown to dissociate PP2A from alpha-4 and inhibit proliferation. This result suggests an alternate positive regulatory role of PP2A in cell proliferation. PP2A is also known as serine/threonine-protein phosphatase 2A catalytic subunit beta isoform, PP2A-beta, and PP2CB. |
| PPP5C PPP5C is the protein phosphatase 5 catalytic unit that is a member of the large PPP family of serine/threonine protein phosphatases. PPP5C plays a role in mediating stress-activated signaling pathways and the DNA damage response. Unlike PP1, PP2A, and PPP4, which function as dimeric or trimeric enzymes, PPP5 functions as a monomer. PPP5 exists as a regulatory N-terminal tetratricopeptide repeat (TPR) domain fused to a C-terminal phosphatase catalytic domain. PPP5C has been demonstrated to associate with and regulate ATM and DNA-PK. PPP5C is also known as serine/threonine-protein phosphatase 5, PP5, protein phosphatase T, PP-T, PPT, PPP5, and FLJ36922. |
| Rad17 Rad17 is a cell cycle checkpoint protein that associates with the RFC complex to recruit the 9-1-1 complex (Rad9, Hus1, Rad1) to sites of DNA damage. At DNA lesions, Rad17 and RFC aid in the activation of Chk2 by ATM and ATRIP to trigger the checkpoint signaling cascade for G2 arrest. Alternate names for Rad17 include cell cycle checkpoint protein RAD17, hRad17, RF-C/activator 1 homolog, R24L, and CCYC. |
| Rad50 Rad50 is a component of the Mre11-Rad50-Nbs1 (MRN) complex that repairs DNA double strand breaks during DNA damage and homologous recombination and activates the S-phase checkpoint. Rad50 shows structural similarity to the structural maintenance of chromosomes (SMC) family of proteins. Rad50 has been shown to directly interact with BRCA2, TERF2IP, and ATM. Alternate designations for Rad50 include DNA repair protein RAD50, hRAD50, and RAD50-2. |
| RPA32 Replication protein A (RPA) is a multisubunit complex that carries out DNA mismatch repair (MMR) in association with MSH2 (a subunit of human MutS heterodimers), MLH1 (a subunit of human MutL heterodimers), PCNA, and DNA polymerase-delta. RPA is composed of a heterotrimer that includes subunits of 70 kDa (RPA1), 32kDa (RPA2), and 14kDa (RPA3). RPA2, the 32kDa subunit, is phosphorylated by the cdc2 family of kinases when cells enter S-phase and in response to DNA damage by ATM, ATR, and DNA-PK. Alternate names for RPA32 include replication protein A 32kDa subunit, RP-A, RF-A, replication factor-A protein 2, p32, p34, RPA2, REPA2, and RPA32. |
| SMC1 Structural maintenance of chromosomes (SMC) proteins are part of the cohesin and condensin multisubunit complexes that play a critical role in chromosome organization, segregation, gene regulation, and DNA repair. The core cohesin complex includes a heterodimer of SMC1 and SMC3 that functions by forming a ring-like structure that holds sister chromatids together. Cohesin is important to sister chromatid separation and segregation during mitosis and meiosis and also plays a role in double-strand break repair by homologous recombination. Alternate designations for SMC1 include SMC1-alpha protein, SMC1A, DXS423E, KIAA0178, SB1.8, SMC1L1, MGC138332, and DKFZp686L19178. |
| SP1 Specificity protein 1 (Sp1) is the original member of the Sp1-like/KLF family of zinc-finger transcription factors that binds GC-rich DNA elements to regulate transcription of genes involved in a variety of cellular functions. Sp-1 interacts with coactivators such as p300/CBP, TAFII130, and CRSP. |
| TRF2 Telomeric repeat binding factor (TRF2) is a ubiquitously expressed protein that localizes at chromosome ends during all phases of the cell cycle and binds directly to TTAGGG repeats. TRF2 functions to protect telomeres as being perceived as sites of DNA damage. TRF2 interacts with several proteins at telomeres, such as Rap1, Mre11, Rad50, and NBS1. TRF2 is also known as TTAGGG repeat-binding factor 2, telomeric DNA-binding protein, TERF2, and TRBF2. |
| WRN The protein product of the Werner’s syndrome (WRN) gene is the Werner syndrome ATP-dependent helicase. WRN is part of the ReqQ family of helicases that unwind DNA in preparation for replication, transcription, and repair. WRN appears to play a versatile role in cellular processes including DNA replication, transcription and the maintenance of genomic integrity. WRN is also known as RECQ3, RECQL2, RECQL3, and DKFZp686C2056. |
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