ATM serine/threonine kinase or Ataxia-telangiectasia mutated, symbol ATM, 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
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and sub ...
arrest,
DNA repair
DNA repair is 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 radiation can cause DNA d ...
or
apoptosis. Several of these targets, including
p53,
CHK2
CHEK2 (Checkpoint kinase 2) is a tumor suppressor gene that encodes the protein CHK2, a serine-threonine kinase. CHK2 is involved in DNA repair, cell cycle arrest or apoptosis in response to DNA damage. Mutations to the CHEK2 gene have been linke ...
,
BRCA1
Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a ...
,
NBS1 and
H2AX
H2A histone family member X (usually abbreviated as H2AX) is a type of histone protein from the H2A family encoded by the ''H2AFX'' gene. An important phosphorylated form is γH2AX (S139), which forms when double-strand breaks appear.
In humans ...
are
tumor suppressors.
In 1995, the gene was discovered by Yosef Shiloh who named its product ATM since he found that its mutations are responsible for the disorder
ataxia–telangiectasia. In 1998, the Shiloh and
Kastan laboratories independently showed that ATM is a protein kinase whose activity is enhanced by DNA damage.
Introduction
Throughout the
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and sub ...
DNA is monitored for damage. Damages result from errors during
replication, by-products of metabolism, general toxic drugs or
ionizing radiation. The cell cycle has different
DNA damage checkpoints, which inhibit the next or maintain the current
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and sub ...
step. There are two main checkpoints, the G1/S and the G2/M, during the cell cycle, which preserve correct progression. ATM plays a role in cell cycle delay after DNA damage, especially after
double-strand breaks (DSBs).
ATM is recruited to sites of double strand breaks by DSB sensor proteins, such as the MRN complex. After being recruited, it phosphorylates
NBS1, along other DSB repair proteins. These modified mediator proteins then amplify the DNA damage signal, and transduce the signals to downstream effectors such as
CHK2
CHEK2 (Checkpoint kinase 2) is a tumor suppressor gene that encodes the protein CHK2, a serine-threonine kinase. CHK2 is involved in DNA repair, cell cycle arrest or apoptosis in response to DNA damage. Mutations to the CHEK2 gene have been linke ...
and
p53.
Structure
The ATM gene codes for a 350 kDa protein consisting of 3056 amino acids. ATM belongs to the superfamily of
phosphatidylinositol 3-kinase-related kinases (PIKKs). The PIKK superfamily comprises six Ser/Thr-protein kinases that show a sequence similarity to
phosphatidylinositol 3-kinase
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
s (PI3Ks). This protein kinase family includes
ATR (ATM- and RAD3-related),
DNA-PKcs (DNA-dependent protein kinase catalytic subunit) and
mTOR (mammalian target of rapamycin). Characteristic for ATM are five domains. These are from N-terminus to C-terminus the
HEAT repeat domain, the FRAP-ATM-
TRRAP (FAT) domain, the kinase domain (KD), the PIKK-regulatory domain (PRD) and the FAT-C-terminal (FATC) domain. The HEAT repeats directly bind to the C-terminus of
NBS1. The FAT domain interacts with ATM's kinase domain to stabilize the C-terminus region of ATM itself. The KD domain resumes kinase activity, while the PRD and the FATC domain regulate it. Although no structure for ATM has been solved, the overall shape of ATM is very similar to
DNA-PKcs and is composed of a head and a long arm that is thought to wrap around double-stranded DNA after a conformational change. The entire N-terminal domain together with the FAT domain are predicted to adopt an α-helical structure, which was found by sequence analysis. This α-helical structure is believed to form a
tertiary structure, which has a curved, tubular shape present for example in the
Huntingtin protein, which also contains HEAT repeats. FATC is the C-terminal domain with a length of about 30 amino acids. It is highly conserved and consists of an
α-helix
The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ...
followed by a sharp turn, which is stabilized by a
disulfide bond.
Function
A complex of the three proteins
MRE11,
RAD50 and
NBS1 (
XRS2 in yeast), called the
MRN complex in humans, recruits ATM to
double strand breaks (DSBs) and holds the two ends together. ATM directly interacts with the
NBS1 subunit and phosphorylates the histone variant
H2AX
H2A histone family member X (usually abbreviated as H2AX) is a type of histone protein from the H2A family encoded by the ''H2AFX'' gene. An important phosphorylated form is γH2AX (S139), which forms when double-strand breaks appear.
In humans ...
on Ser139.
This phosphorylation generates binding sites for adaptor proteins with a
BRCT domain
BRCA1 C Terminus (BRCT) domain is a family of evolutionarily related proteins. It is named after the C-terminal domain of BRCA1, a DNA-repair protein that serves as a marker of breast cancer susceptibility.
The BRCT domain is found predominant ...
. These adaptor proteins then recruit different factors including the effector protein kinase
CHK2
CHEK2 (Checkpoint kinase 2) is a tumor suppressor gene that encodes the protein CHK2, a serine-threonine kinase. CHK2 is involved in DNA repair, cell cycle arrest or apoptosis in response to DNA damage. Mutations to the CHEK2 gene have been linke ...
and the tumor suppressor
p53. The ATM-mediated DNA damage response consists of a rapid and a delayed response. The effector kinase CHK2 is phosphorylated and thereby activated by ATM. Activated CHK2 phosphorylates phosphatase
CDC25A, which is degraded thereupon and can no longer dephosphorylate
CDK1-
cyclin B, resulting in cell-cycle arrest. If the DSB can not be repaired during this rapid response, ATM additionally phosphorylates
MDM2 and
p53 at Ser15.
p53 is also phosphorylated by the effector kinase CHK2. These phosphorylation events lead to stabilization and activation of p53 and subsequent transcription of numerous p53 target genes including CDK inhibitor
p21 which lead to long-term cell-cycle arrest or even apoptosis.
The protein kinase ATM may also be involved in mitochondrial homeostasis, as a regulator of mitochondrial autophagy (mitophagy) whereby old, dysfunctional mitochondria are removed.
Increased ATM activity also occurs in viral infection where ATM is activated early during dengue virus infection as part of autophagy induction and ER stress response.
Regulation
A functional
MRN complex
The MRN complex (MRX complex in yeast) is a protein complex consisting of Mre11, Rad50 and Nbs1 (also known as Nibrin in humans and as Xrs2 in yeast). In eukaryotes, the MRN/X complex plays an important role in the initial processing of double-st ...
is required for ATM activation after DSBs. The complex functions upstream of ATM in mammalian cells and induces conformational changes that facilitate an increase in the affinity of ATM towards its substrates, such as CHK2 and p53.
Inactive ATM is present in the cells without DSBs as dimers or multimers. Upon DNA damage, ATM autophosphorylates on residue Ser1981. This phosphorylation provokes dissociation of ATM dimers, which is followed by the release of active ATM monomers.
Further autophosphorylation (of residues Ser367 and Ser1893) is required for normal activity of the ATM kinase. Activation of ATM by the
MRN complex is preceded by at least two steps, i.e. recruitment of ATM to DSB ends by the mediator of DNA damage checkpoint protein 1 (
MDC1
Mediator of DNA damage checkpoint protein 1 is a 2080 amino acid long protein that in humans is encoded by the ''MDC1'' gene located on the short arm (p) of chromosome 6. MDC1 protein is a regulator of the Intra-S phase and the G2/M cell cycle chec ...
) which binds to
MRE11, and the subsequent stimulation of kinase activity with the
NBS1 C-terminus.
The three domains FAT, PRD and FATC are all involved in regulating the activity of the KD kinase domain. The FAT domain interacts with ATM's KD domain to stabilize the C-terminus region of ATM itself. The FATC domain is critical for kinase activity and highly sensitive to mutagenesis. It mediates protein-protein interaction for example with the histone
acetyltransferase TIP60 (HIV-1 Tat interacting protein 60 kDa), which acetylates ATM on residue Lys3016. The acetylation occurs in the C-terminal half of the PRD domain and is required for ATM kinase activation and for its conversion into monomers. While deletion of the entire PRD domain abolishes the kinase activity of ATM, specific small deletions show no effect.
Germline mutations and cancer risk
People who carry a
heterozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
...
ATM mutation have increased risk of mainly
pancreatic cancer,
prostate cancer,
stomach cancer and
invasive ductal carcinoma of the breast.
Homozygous ATM mutation confers the disease
ataxia–telangiectasia (AT), a rare human disease characterized by cerebellar degeneration, extreme cellular sensitivity to radiation and a predisposition to cancer. All AT patients contain mutations in the ATM gene. Most other AT-like disorders are defective in genes encoding the
MRN protein complex. One feature of the ATM protein is its rapid increase in kinase activity immediately following double-strand break formation.
The phenotypic manifestation of AT is due to the broad range of substrates for the ATM kinase, involving DNA repair,
apoptosis, G
1/S, intra-S checkpoint and G
2/M checkpoints, gene regulation,
translation
Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...
initiation, and
telomere maintenance.
Therefore, a defect in ATM has severe consequences in repairing certain types of damage to DNA, and
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
may result from improper repair. AT patients have an increased risk for breast cancer that has been ascribed to ATM's interaction and phosphorylation of
BRCA1
Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a ...
and its associated proteins following DNA damage.
Somatic ATM mutations in sporadic cancers
Mutations in the ATM gene are found at relatively low frequencies in sporadic cancers. According to ''COSMIC'', the ''Catalogue Of Somatic Mutations In Cancer'', the frequencies with which heterozygous mutations in ATM are found in common cancers include 0.7% in 713 ovarian cancers, 0.9% in central nervous system cancers, 1.9% in 1,120 breast cancers, 2.1% in 847 kidney cancers, 4.6% in colon cancers, 7.2% among 1,040 lung cancers and 11.1% in 1790 hematopoietic and lymphoid tissue cancers.
Certain kinds of
leukemia
Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...
s and
lymphoma
Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include en ...
s, including
mantle cell lymphoma,
T-ALL, atypical
B cell chronic lymphocytic leukemia, and
T-PLL are also associated with ATM defects.
[
*] A comprehensive literature search on ATM deficiency in pancreatic cancer, that captured 5,234 patients, estimated that the total prevalence of germline or somatic ATM mutations in pancreatic cancer was 6.4%. ATM mutations may serve as predictive biomarkers of response for certain therapies, since preclinical studies have found that ATM deficiency can sensitise some cancer types to
ATR inhibition.
Frequent epigenetic deficiencies of ATM in cancers
ATM is one of the DNA repair genes frequently
hypermethylated
In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...
in its promoter region in various cancers (see table of such genes in
Cancer epigenetics). The promoter methylation of ATM causes reduced protein or
mRNA expression of ATM.
More than 73% of brain tumors were found to be methylated in the ATM gene promoter and there was strong inverse correlation between ATM promoter methylation and its protein expression (p < 0.001).
The ATM gene promoter was observed to be hypermethylated in 53% of small (impalpable) breast cancers
and was hypermethylated in 78% of stage II or greater breast cancers with a highly significant correlation (P = 0.0006) between reduced ATM mRNA abundance and aberrant methylation of the ATM gene promoter.
In non-small cell lung cancer (NSCLC), the ATM promoter methylation status of paired tumors and surrounding histologically uninvolved lung tissue was found to be 69% and 59%, respectively. However, in more advanced NSCLC the frequency of ATM promoter methylation was lower at 22%.
The finding of ATM promoter methylation in surrounding histologically uninvolved lung tissue suggests that ATM deficiency may be present early in a
field defect leading to progression to NSCLC.
In squamous cell carcinoma of the head and neck, 42% of tumors displayed ATM promoter methylation.
DNA damage appears to be the primary underlying cause of cancer,
and deficiencies in DNA repair likely underlie many forms of cancer.
If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage may increase
mutational errors during
DNA replication
In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritan ...
due to error-prone
translesion synthesis. Excess DNA damage may also increase
epigenetic alterations due to errors during DNA repair.
Such mutations and epigenetic alterations may give rise to cancer. The frequent epigenetic deficiency of ATM in a number of cancers likely contributed to the progression of those cancers.
Meiosis
ATM functions during
meiotic prophase.
The wild-type ATM gene is expressed at a four-fold increased level in human
testes compared to
somatic cells (such as skin fibroblasts).
In both mice and humans, ATM deficiency results in female and male
infertility. Deficient ATM expression causes severe meiotic disruption during
prophase I.
In addition, impaired ATM-mediated DNA DSB repair has been identified as a likely cause of aging of mouse and human oocytes.
Expression of the ATM gene, as well as other key DSB repair genes, declines with age in mouse and human oocytes and this decline is paralleled by an increase of DSBs in primordial follicles.
These findings indicate that ATM-mediated homologous recombinational repair is a crucial function of meiosis.
Interactions
Ataxia telangiectasia mutated has been shown to
interact
Advocates for Informed Choice, doing business as, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex trai ...
with:
*
Abl gene,
* BRCA1
Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a ...
,
* Bloom syndrome protein,
* DNA-PKcs,
* FANCD2,
* MRE11A,[
* Nibrin,]
* P53,
* RAD17,
* RAD51,
* RBBP8
Retinoblastoma-binding protein 8 is a protein that in humans is encoded by the ''RBBP8'' gene.
Function
The protein encoded by this gene is a ubiquitously expressed nuclear protein. It is found among several proteins that bind directly to reti ...
,
* RHEB,
* RRM2B
Ribonucleotide-diphosphate reductase subunit M2 B is an enzyme that in humans is encoded by the ''RRM2B'' gene. The gene encoding the RRM2B protein is located on chromosome 8, at position 8q23.1. The gene and its products are also known by designa ...
,
* SMC1A
* TERF1, and
* TP53BP1.
Tefu
The Tefu protein of ''Drosophila melanogaster
''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the " vinegar fly" or "pomace fly". Starting with ...
'' is a structural and functional homolog of the human ATM protein. Tefu, like ATM, is required for DNA repair
DNA repair is 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 radiation can cause DNA d ...
and normal levels of meiotic recombination in oocyte
An oocyte (, ), oöcyte, or ovocyte is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The female ...
s.
See also
* Ataxia telangiectasia
Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...
* Ataxia telangiectasia and Rad3 related
References
Further reading
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External links
* https://web.archive.org/web/20060107000211/http://www.hprd.org/protein/06347
''Drosophila'' ''telomere fusion'' - The Interactive Fly
GeneReviews/NCBI/NIH/UW entry on Ataxia telangiectasia
OMIM entries on Ataxia telangiectasia
*
*
{{DEFAULTSORT:ATM serine threonine kinase
Proteins
EC 2.7.11