Ataxia telangiectasia and Rad3 related
Encyclopedia
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.
/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 fork
s 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 related to a second checkpoint-activating kinase, ATM
, which is activated by double strand breaks in DNA or chromatin disruption.
, a rare human disorder that shares some characteristics with ataxia telangiectasia
, which results from ATM
mutation.
with RAD17
, Histone deacetylase 2
, MSH2
, CHD4
, BRCA1
, P53
and RHEB
.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that in humans is encoded by the ATR gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. ATR belongs to the phosphatidylinositol 3-kinase-related kinase
Phosphatidylinositol 3-kinase-related kinase
Phosphatidylinositol 3-kinase-related kinases are a family of Ser/Thr-protein kinases with sequence similarity to phosphatidylinositol-3 kinases .- Members :The human PIKK family includes six members:- Structure :...
protein family.
Function
ATR is a serineSerine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
/threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
-specific protein kinase
Protein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...
that is involved in sensing DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
damage and activating the DNA damage checkpoint
Cell cycle checkpoint
Cell cycle checkpoints are control mechanisms that ensure the fidelity of cell division in eukaryotic cells. These checkpoints verify whether the processes at each phase of the cell cycle have been accurately completed before progression into the next phase...
, leading to cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
arrest. ATR is activated in response to persistent single-stranded DNA, which is a common intermediate formed during DNA damage detection and repair
DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
. Single-stranded DNA occurs at stalled replication fork
Replication fork
The replication fork is a structure that forms within the nucleus during DNA replication. It is created by helicases, which break the hydrogen bonds holding the two DNA strands together. The resulting structure has two branching "prongs", each one made up of a single strand of DNA...
s and as an intermediate in DNA repair
DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
pathways such as nucleotide excision repair
Nucleotide excision repair
Nucleotide excision repair is a DNA repair mechanism. DNA constantly requires repair due to damage that can occur to bases from a vast variety of sources including chemicals, radiation and other mutagens...
and homologous recombination repair. ATR works with a partner protein called ATRIP to recognize single-stranded DNA coated with RPA
Replication protein A
Replication protein A is a protein that binds single-stranded DNA in eukaryotic cells. During DNA replication, RPA prevents single-stranded DNA from winding back on itself or from forming secondary structures. This keeps DNA unwound for the polymerase to replicate it...
. Once ATR is activated, it phosphorylates Chk1, initiating a signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
cascade that culminates in cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
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
Ataxia telangiectasia mutated
Ataxia telangiectasia mutated is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks. It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis...
, which is activated by double strand breaks in DNA or chromatin disruption.
Clinical significance
Mutations in ATR are responsible for Seckel syndromeSeckel syndrome
The Seckel syndrome or microcephalic primordial dwarfism is a congenital nanosomic disorder....
, a rare human disorder that shares some characteristics with ataxia telangiectasia
Ataxia telangiectasia
Ataxia telangiectasia is a rare, neurodegenerative, inherited disease that affects many parts of the body and causes severe disability. Ataxia refers to poor coordination and telangiectasia to small dilated blood vessels, both of which are hallmarks of the disease...
, which results from ATM
Ataxia telangiectasia mutated
Ataxia telangiectasia mutated is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks. It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis...
mutation.
Interactions
Ataxia telangiectasia and Rad3 related has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with RAD17
RAD17
Cell cycle checkpoint protein RAD17 is a protein that in humans is encoded by the RAD17 gene.-Interactions:RAD17 has been shown to interact with RAD9A, RAD1 homolog, POLE, NHP2L1, Ataxia telangiectasia mutated, HUS1 and Ataxia telangiectasia and Rad3 related.-Further reading:...
, Histone deacetylase 2
Histone deacetylase 2
Histone deacetylase 2 is an enzyme that in humans is encoded by the HDAC2 gene.-Interactions:Histone deacetylase 2 has been shown to interact with CHD3, MTA1, FKBP3, CHD4, RCOR1, Retinoblastoma protein, CDC20, RBBP4, CDH1, EED, GTF2I, Host cell factor C1, PHF21A, BUB3, MXD1, HDAC10, RELA, Sp3...
, MSH2
MSH2
MSH2 is a gene commonly associated with Hereditary nonpolyposis colorectal cancer.-Interactions:MSH2 has been shown to interact with Exonuclease 1, MSH3, MSH6, CHEK2, MAX, Ataxia telangiectasia and Rad3 related and BRCA1.-Further reading:...
, CHD4
CHD4
Chromodomain-helicase-DNA-binding protein 4 is an enzyme that in humans is encoded by the CHD4 gene.-Interactions:CHD4 has been shown to interact with HDAC1, Histone deacetylase 2, MTA2, SATB1 and Ataxia telangiectasia and Rad3 related....
, BRCA1
BRCA1
BRCA1 is a human caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA. The first evidence for the existence of the gene was provided by the King laboratory at UC Berkeley in 1990...
, P53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
and RHEB
RHEB
GTP-binding protein Rheb also known as Ras homolog enriched in brain is a protein that in humans is encoded by the RHEB gene.- Function :Rheb is a recently discovered member of the Ras superfamily that may be involved in neural plasticity...
.