<i>Atm</i> Inactivation Results in Aberrant Telomere Clustering during Meiotic Prophase

“…The first report describing the association of ATM with DNA damage repair and telomere metabolism was described in 1995 (Pandita et al, 1995). Subsequently, the role of ATM in telomere function became clear by comparing the meiotic prophase 1 of spermatocytes from mice with and without ATM, revealing that ATM inactivation results in aberrant telomere clustering during meiotic prophase (Pandita et al, 1999, 2007; Scherthan et al, 2000; Pandita, 2001, 2002a, 2003). These studies prompted several groups to determine whether ATM is physically associated with telomeres.…”

Section: Factors Common In Telomere Maintenance and Dna Damage Responsementioning

confidence: 99%

“…They consist of an array of simple DNA repeats at the extreme end of the chromosome, with a more complex array of repeats immediately adjacent to it. Telomere behavior is abnormal in ATM deficient cells, both somatic as well as germ cells (Pandita et al, 1995, 1996, 1999, 2007; Pandita and Dhar, 2000; Scherthan et al, 2000; Hande et al, 2001; Pandita, 2001, 2002a, b, 2003), but the precise mechanism by which ATM regulates telomere structure and function is not known. Recent studies suggest that ATM interacts with various chromatin modifying factors that could influence telomere function (Fig.…”

mentioning

confidence: 99%

Telomeres, histone code, and DNA damage response

Misri

Pandita

Kumar

et al. 2008

Cytogenet Genome Res

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Genomic stability is maintained by telomeres, the end terminal structures that protect chromosomes from fusion or degradation. Shortening or loss of telomeric repeats or altered telomere chromatin structure is correlated with telomere dysfunction such as chromosome end-to-end associations that could lead to genomic instability and gene amplification. The structure at the end of telomeres is such that its DNA differs from DNA double strand breaks (DSBs) to avoid nonhomologous end-joining (NHEJ), which is accomplished by forming a unique higher order nucleoprotein structure. Telomeres are attached to the nuclear matrix and have a unique chromatin structure. Whether this special structure is maintained by specific chromatin changes is yet to be thoroughly investigated. Chromatin modifications implicated in transcriptional regulation are thought to be the result of a code on the histone proteins (histone code). This code, involving phosphorylation, acetylation, methylation, ubiquitylation, and sumoylation of histones, is believed to regulate chromatin accessibility either by disrupting chromatin contacts or by recruiting non-histone proteins to chromatin. The histone code in which distinct histone tail-protein interactions promote engagement may be the deciding factor for choosing specific DSB repair pathways. Recent evidence suggests that such mechanisms are involved in DNA damage detection and repair. Altered telomere chromatin structure has been linked to defective DNA damage response (DDR), and eukaryotic cells have evolved DDR mechanisms utilizing proficient DNA repair and cell cycle checkpoints in order to maintain genomic stability. Recent studies suggest that chromatin modifying factors play a critical role in the maintenance of genomic stability. This review will summarize the role of DNA damage repair proteins specifically ataxia-telangiectasia mutated (ATM) and its effectors and the telomere complex in maintaining genome stability.

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“…100). In both somatic and germ cells that are deficient in ATM function, more than 80% of the telomeric DNA is attached to the nuclear matrix, whereas about 50% is attached in control cells (Refs 8,9). 100).…”

Section: Atm Deficiency Influences Telomere Chromatin Structurementioning

confidence: 99%

“…Cells derived from A-T individuals exhibit genomic instability and are hypersensitive to IR and radiomimetic drugs (Refs 2, 3). An abnormal nuclear matrix organisation in A-T cells is suggested by observations of abnormalities in telomerenuclear-matrix association in A-T fibroblasts and germ cells, and aberrant telomere clustering in spermatocytes of mice deficient in the ataxiatelangiectasia mutated protein ('Atm' in mice; 'ATM' in humans) (Refs 8,9,10,11). 4).…”

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confidence: 99%

A multifaceted role for ATM in genome maintenance

Pandita

2003

Expert Rev. Mol. Med.

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The pleiotropic nature of the clinical phenotypes of patients with ataxiatelangiectasia (A-T) -which encompass cerebellar degeneration (leading to ataxia), gonadal atrophy, and cancer predisposition -suggests multiple functions of the gene responsible for the disease. The ataxia-telangiectasia mutated gene product (ATM), whose loss of function is responsible for ataxiatelangiectasia, is a protein kinase that interacts with several substrates and is implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination, cell-cycle control and telomere maintenance. This review focuses on the critical roles that ATM appears to play in cell-cycle checkpoints, DNA repair, telomere metabolism and oxidative stress, indicating how defects in these processes might lead to ataxia-telangiectasia.

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Atm Inactivation Results in Aberrant Telomere Clustering during Meiotic Prophase

Cited by 13 publications

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Telomeres, histone code, and DNA damage response

A multifaceted role for ATM in genome maintenance

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