Ataxia telangiectasia and Rad3 related
|, ATR serine/threonine kinase, FCTCS, FRP1, MEC1, SCKL, SCKL1|
Serine/threonine-protein kinase ATR also known as ataxia telangiectasia and Rad3-related protein (ATR) or FRAP-related protein 1 (FRP1) is an enzyme that, in humans, is encoded by the ATR gene. ATR belongs to the phosphatidylinositol 3-kinase-related kinase protein family. ATR is activated in response to single strand breaks.
ATR is a serine/threonine-specific protein kinase that is involved in sensing DNA damage and activating the DNA damage checkpoint, leading to cell cycle arrest. ATR is activated in response to persistent single-stranded DNA, which is a common intermediate formed during DNA damage detection and repair. Single-stranded DNA occurs at stalled replication forks and as an intermediate in DNA repair pathways such as nucleotide excision repair and homologous recombination repair. ATR works with a partner protein called ATRIP to recognize single-stranded DNA coated with RPA. Once ATR is activated, it phosphorylates Chk1, initiating a signal transduction cascade that culminates in cell cycle arrest. In addition to its role in activating the DNA damage checkpoint, ATR is thought to function in unperturbed DNA replication.
ATR is also linked to familial cutaneous telangiectasia and cancer syndrome.
ATR/ChK1 inhibitors can potentiate the effect of DNA cross-linking agents. 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.
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. Furthermore, there are dramatic reductions with age in tissue-specific stem and progenitor cells, and exhaustion of tissue renewal and homeostatic capacity. There was also an early and permanent loss of spermatogenesis. However, there was no significant increase in tumor risk.
In humans, hypomorphic mutations (partial loss of gene function) in the ATR gene are linked to Seckel syndrome, a condition characterized by proportionate dwarfism, developmental delay, marked microcephaly, dental malocclusion and thoracic kyphosis. A senile or progeroid appearance has also been frequently noted in Seckel patients.
Homologous recombinational repair
Somatic cells of mice deficient in ATR have a decreased frequency of homologous recombination and an increased level of chromosomal damage. 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. During mitosis in Drosophila DNA damages caused by exogenous agents are repaired by an 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 , and methyl methanesulfonate. Deficiency of mei-41(ATR) also causes reduced spontaneous allelic recombination (crossing over) during meiosis suggesting that wild-type mei-41(ATR) is employed in recombinational repair of spontaneous DNA damages during meiosis.
Ataxia telangiectasia and Rad3 related has been shown to interact with:
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