Ataxia telangiectasia and Rad3 related
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Location (UCSC) | Chr 3: 142.45 – 142.58 Mb | Chr 9: 95.74 – 95.83 Mb | |||||||
PubMed search | [3] | [4] |
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Serine/threonine-protein kinase ATR, also known as ataxia telangiectasia and Rad3-related protein (ATR) or FRAP-related protein 1 (FRP1), is an
Function
ATR is a
It is not just ssDNA that activates ATR, though the existence of RPA associated ssDNA is important. Instead, ATR activation is heavily dependent on the existence of all the proteins previously described, that colocalize around the site of DNA damage. An experiment where RAD9, ATRIP, and TOPBP1 were overexpressed proved that these proteins alone were enough to activate ATR in the absence of ssDNA, showing their importance in triggering this pathway.[11]
Once ATR is activated, it phosphorylates
ATR is related to a second checkpoint-activating kinase,
ATR as an essential protein
Mutations in ATR are very uncommon. The total knockout of ATR is responsible for early death of mouse embryos, showing that it is a protein with essential life functions. It is hypothesized that this could be related to its likely activity in stabilizing Okazaki fragments on the lagging strands of DNA during replication, or due to its job stabilizing stalled replication forks, which naturally occur. In this setting, ATR is essential to preventing fork collapse, which would lead to extensive double strand breakage across the genome. The accumulation of these double strand breaks could lead to cell death.[11]
Clinical significance
Mutations in ATR are responsible for
ATR is also linked to familial cutaneous telangiectasia and cancer syndrome.[16]
Inhibitors
ATR/ChK1 inhibitors can potentiate the effect of DNA cross-linking agents such as cisplatin and nucleoside analogues such as gemcitabine.[17] The first clinical trials using inhibitors of ATR have been initiated by AstraZeneca, preferably in ATM-mutated chronic lymphocytic leukaemia (CLL), prolymphocytic leukaemia (PLL) or B-cell lymphoma patients and by Vertex Pharmaceuticals in advanced solid tumours.[18] ATR provided and exciting point for potential targeting in these solid tumors, as many tumors function through activating the DNA damage response. These tumor cells rely on pathways like ATR to reduce replicative stress within the cancerous cells that are uncontrollably dividing, and thus these same cells could be very susceptible to ATR knockout.[19] In ATR-Seckel mice, after exposure to cancer-causing agents, the damage DNA damage response pathway actually conferred resistance to tumor development (6). After many screens to identify specific ATR inhibitors, currently four made it into phase I or phase II clinical trials since 2013; these include AZD6738, M6620 (VX-970), BAY1895344[20] (Elimusertib).[21] and M4344 (VX-803) (10). These ATR inhibitors work to help the cell proceed through p53 independent apoptosis, as well as force mitotic entry that leads to mitotic catastrophe.[19]
One study by Flynn et al. found that ATR inhibitors work especially well in cancer cells which rely on the alternative lengthening of telomeres (ALT) pathway. This is due to RPA presence when ALT is being established, which recruits ATR to regulate homologous recombination. This ALT pathway was extremely fragile with ATR inhibition and thus using these inhibitors to target this pathway that keeps cancer cell immortal could provide high specificity to stubborn cancer cells.[22]
Examples include
Aging
Deficiency of ATR expression in adult mice leads to the appearance of age-related alterations such as hair graying, hair loss, kyphosis (rounded upper back), osteoporosis and thymic involution.[23] Furthermore, there are dramatic reductions with age in tissue-specific stem and progenitor cells, and exhaustion of tissue renewal and homeostatic capacity.[23] There was also an early and permanent loss of spermatogenesis. However, there was no significant increase in tumor risk.
Seckel syndrome
In humans, hypomorphic mutations (partial loss of gene function) in the ATR gene are linked to Seckel syndrome, an autosomal recessive condition characterized by proportionate dwarfism, developmental delay, marked microcephaly, dental malocclusion and thoracic kyphosis.[24] A senile or progeroid appearance has also been frequently noted in Seckel patients.[23] For many years, the mutation found in the two families first diagnosed with Seckel Syndrome were the only mutations known to cause the disease.
In 2012, Ogi and colleagues discovered multiple new mutations that also caused the disease. One form of the disease, which involved mutation in genes encoding the ATRIP partner protein, is considered more severe that the form that was first discovered.[25] This mutation led to severe microcephaly and growth delay, microtia, micrognathia, dental crowding, and skeletal issues (evidenced in unique patellar growth). Sequencing revealed that this ATRIP mutation occurred most likely due to missplicing which led to fragments of the gene without exon 2. The cells also had a nonsense mutation in exon 12 of the ATR gene which led to a truncated ATR protein. Both of these mutations resulted in lower levels of ATR and ATRIP than in wild-type cells, leading to insufficient DNA damage response and the severe form of Seckel Syndrome noted above.[25]
Researchers also found that heterozygous mutations in ATR were responsible for causing Seckel Syndrome. Two novel mutations in one copy of the ATR gene caused under-expression of both ATR and ATRIP.[25]
Homologous recombinational repair
Somatic cells of mice deficient in ATR have a decreased frequency of homologous recombination and an increased level of chromosomal damage.[26] This finding implies that ATR is required for homologous recombinational repair of endogenous DNA damage.
Drosophila mitosis and meiosis
Mei-41 is the Drosophila ortholog of ATR.[27] During mitosis in Drosophila DNA damages caused by exogenous agents are repaired by a homologous recombination process that depends on mei-41(ATR). Mutants defective in mei-41(ATR) have increased sensitivity to killing by exposure to the DNA damaging agents UV ,[28] and methyl methanesulfonate.[28][29] Deficiency of mei-41(ATR) also causes reduced spontaneous allelic recombination (crossing over) during meiosis[28] suggesting that wild-type mei-41(ATR) is employed in recombinational repair of spontaneous DNA damages during meiosis.
Interactions
Ataxia telangiectasia and Rad3-related protein has been shown to
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000175054 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032409 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 8610130.
- PMID 8978690.
- PMID 14729973.
- PMID 15189136.
- S2CID 30138518.
- ^ OCLC 769544943.
- ^ PMID 18594563.
- ^ S2CID 21989146.
- PMID 12629044.
- S2CID 4403303.
- PMID 12640452.
- ^ "OMIM Entry - # 614564 - CUTANEOUS TELANGIECTASIA AND CANCER SYNDROME, FAMILIAL; FCTCS". omim.org.
- S2CID 220931196.
- S2CID 20714812.
- ^ S2CID 49189972.
- ^ "The Novel ATR Inhibitor BAY 1895344 Is Efficacious as Monotherapy and Combined with DNA Damage–Inducing or Repair–Compromising Therapies in Preclinical Cancer Models". Molecular Cancer Therapeutics.
- S2CID 253524852.
- PMID 25593184.
- ^ PMID 18371340.
- S2CID 7779574.
- ^ PMID 23144622.
- PMID 24675793.
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- ^ PMID 825857.
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- ^ PMID 10608806.
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- PMID 11278964.
- ^ PMID 10545197.
- PMID 14657349.
- PMID 15159397.
- S2CID 4429058.
- S2CID 3078706.
Further reading
- Giaccia AJ, Kastan MB (October 1998). "The complexity of p53 modulation: emerging patterns from divergent signals". Genes & Development. 12 (19): 2973–2983. PMID 9765199.
- Shiloh Y (February 2001). "ATM and ATR: networking cellular responses to DNA damage". Current Opinion in Genetics & Development. 11 (1): 71–77. PMID 11163154.
- Kastan MB, Lim DS (December 2000). "The many substrates and functions of ATM". Nature Reviews. Molecular Cell Biology. 1 (3): 179–186. S2CID 10691352.
- Abraham RT (2005). "The ATM-related kinase, hSMG-1, bridges genome and RNA surveillance pathways". DNA Repair. 3 (8–9): 919–925. PMID 15279777.
- Li L, Li HS, Pauza CD, Bukrinsky M, Zhao RY (2006). "Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions". Cell Research. 15 (11–12): 923–934. PMID 16354571.
External links
- Drosophila meiotic-41 - The Interactive Fly
- Human ATR genome location and ATR gene details page in the UCSC Genome Browser.