ATM serine/threonine kinase

Source: Wikipedia, the free encyclopedia.
This article is about the ATM protein. For the ATM cell type, see adipose tissue macrophages.
ATM
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000149311

ENSMUSG00000034218

UniProt

Q13315

Q62388

RefSeq (mRNA)

NM_007499

RefSeq (protein)

NP_000042
NP_001338763
NP_001338764
NP_001338765
NP_000042.3

NP_031525

Location (UCSC)Chr 11: 108.22 – 108.37 MbChr 9: 53.35 – 53.45 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

ATM serine/threonine kinase or Ataxia-telangiectasia mutated, symbol ATM, is a

tumor suppressors
.

In 1995, the gene was discovered by Yosef Shiloh[6] who named its product ATM since he found that its mutations are responsible for the disorder ataxia–telangiectasia.[7] In 1998, the Shiloh and Kastan laboratories independently showed that ATM is a protein kinase whose activity is enhanced by DNA damage.[8][9]

Introduction

Throughout the

CHK2 and p53
.

Structure

The ATM gene codes for a 350 kDa protein consisting of 3056 amino acids.

α-helix.[13]

Schematic illustration of the four known conserved domains in four members of the PIKKs family[13]

Function

A complex of the three proteins

MDM2 and p53 at Ser15.[9] 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.[15]

ATM-mediated two-step response to DNA double strand breaks. In the rapid response activated ATM phosphorylates effector kinase CHK2 which phosphorylates CDC25A, targeting it for ubiquitination and degradation. Therefore, phosphorylated CDK2-Cyclin accumulates and progression through the cell cycle is blocked. In the delayed response ATM phosphorylates the inhibitor of p53, MDM2, and p53, which is also phosphorylated by Chk2. The resulting activation and stabilization of p53 leads to an increased expression of Cdk inhibitor p21, which further helps to keep Cdk activity low and to maintain long-term cell cycle arrest.[15]

The protein kinase ATM may also be involved in mitochondrial homeostasis, as a regulator of mitochondrial autophagy (mitophagy) whereby old, dysfunctional mitochondria are removed.[16] 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.[17]

Regulation

A functional MRN complex 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.[10] 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.

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.[13]

Germline mutations and cancer risk

Further information: Ataxia–telangiectasia

People who carry a

MRN protein complex. One feature of the ATM protein is its rapid increase in kinase activity immediately following double-strand break formation.[20][8] The phenotypic manifestation of AT is due to the broad range of substrates for the ATM kinase, involving DNA repair, apoptosis, G1/S, intra-S checkpoint and G2/M checkpoints, gene regulation, translation initiation, and telomere maintenance.[21] Therefore, a defect in ATM has severe consequences in repairing certain types of damage to DNA, and cancer 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 and its associated proteins following DNA damage.[22]

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.

T-PLL are also associated with ATM defects.[24] 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%.[25] 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.[26][27][28][29]

Frequent epigenetic deficiencies of ATM in cancers

ATM is one of the DNA repair genes frequently hypermethylated 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).[30]

The ATM gene promoter was observed to be hypermethylated in 53% of small (impalpable) breast cancers[31] 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.[32]

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%.[33] 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.[34]

DNA damage appears to be the primary underlying cause of cancer,

mutational errors during DNA replication due to error-prone translesion synthesis. Excess DNA damage may also increase epigenetic alterations due to errors during DNA repair.[37][38]
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.[39] The wild-type ATM gene is expressed at a four-fold increased level in human testes compared to somatic cells (such as skin fibroblasts).[40] In both mice and humans, ATM deficiency results in female and male infertility. Deficient ATM expression causes severe meiotic disruption during prophase I.[41] In addition, impaired ATM-mediated DNA DSB repair has been identified as a likely cause of aging of mouse and human oocytes.[42] 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.[42] These findings indicate that ATM-mediated homologous recombinational repair is a crucial function of meiosis.

Inhibitors

Several ATM kinase inhibitors are currently known, some of which are already in clinical trials.[43][44][45] One of the first discovered ATM inhibitors is caffeine with an IC50 of 0.2 mM and only a low selectivity within the PIKK family.[46][47] Wortmannin is an irreversible inhibitor of ATM with no selectivity over other related PIKK and PI3K kinases.[48] The most important group of inhibitors are compounds based on the 3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one scaffold. The first important representative is the inhibitor is Dactolisib (NVP-BEZ235), which was first published by Novartis as a selective mTOR/PI3K inhibitor.[49] It was later shown to also inhibit other PIKK kinases such as ATM, DNA-PK and ATR.[50] Various optimisation efforts by AstraZeneca (AZD0156, AZD1390), Merck (M4076) and Dimitrov et al. have led to highly active ATM inhibitors with greater potency.[51][52][53]

Caffeine is an ATM inhibitor with low activity
AZD0156 is highly active ATM inhibitor from AstraZeneca

Interactions

Ataxia telangiectasia mutated has been shown to interact with:

Tefu

The Tefu protein of Drosophila melanogaster is a structural and functional homolog of the human ATM protein.[78] Tefu, like ATM, is required for DNA repair and normal levels of meiotic recombination in oocytes.

See also

References

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  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000034218 – Ensembl, May 2017
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Further reading

External links
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