Ataxia telangiectasia and Rad3 related

Serine/threonine-protein kinase ATR also known as ataxia telangiectasia and Rad3-related protein (ATR) or FRAP-related protein 1 (FRP1) is an is_associated_with::enzyme that, in humans, is encoded by the ATR is_associated_with::gene. ATR belongs to the is_associated_with::phosphatidylinositol 3-kinase-related kinase protein family.

Function
ATR is a is_associated_with::serine/is_associated_with::threonine-specific is_associated_with::protein kinase that is involved in sensing is_associated_with::DNA damage and activating the DNA damage checkpoint, leading to is_associated_with::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 is_associated_with::replication forks and as an intermediate in is_associated_with::DNA repair pathways such as is_associated_with::nucleotide excision repair and is_associated_with::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 is_associated_with::Chk1, initiating a is_associated_with::signal transduction cascade that culminates in is_associated_with::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 related to a second checkpoint-activating kinase, ATM, which is activated by double strand breaks in DNA or chromatin disruption.

Clinical significance
Mutations in ATR are responsible for is_associated_with::Seckel syndrome, a rare human disorder that shares some characteristics with is_associated_with::ataxia telangiectasia, which results from ATM mutation.

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.

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. 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.

Seckel syndrome
In humans, hypomorphic mutations (partial loss of gene function) in the ATR gene are linked to Seckel syndrome, a condition characterized by proportionate is_associated_with::dwarfism, developmental delay, marked is_associated_with::microcephaly, dental is_associated_with::malocclusion and thoracic is_associated_with::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 is_associated_with::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 is_associated_with::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 is_associated_with::methyl methanesulfonate. Deficiency of mei-41(ATR) also causes reduced spontaneous allelic recombination (crossing over) during is_associated_with::meiosis suggesting that wild-type mei-41(ATR) is employed in recombinational repair of spontaneous DNA damages during is_associated_with::meiosis.

Interactions
Ataxia telangiectasia and Rad3 related has been shown to interact with:


 * is_associated_with::BRCA1,
 * is_associated_with::CHD4,
 * HDAC2,
 * is_associated_with::MSH2,
 * is_associated_with::P53
 * is_associated_with::RAD17,  and
 * is_associated_with::RHEB.