A splicing mutation affecting expression of ataxia–telangiectasia and Rad3–related protein (ATR) results in Seckel syndrome

O’Driscoll, Mark; Ruiz‐Pérez, Víctor L.; Woods, C. Geoffrey; Jeggo, Penny A.; Goodship, Judith A.

doi:10.1038/ng1129

Cited by 710 publications

(664 citation statements)

References 20 publications

Supporting

Mentioning

621

Contrasting

Unclassified

Order By: Relevance

“…This may manifest as a hypomorphic mutation similar to ATR mutations associated with Seckel syndrome 45 . Thus, assessing the integrity of the HCLK2 gene in Fanconi anaemia and Seckel cells that cannot be assigned to known complementation groups will be of great clinical importance.…”

Section: Discussionmentioning

confidence: 99%

HCLK2 is essential for the mammalian S-phase checkpoint and impacts on Chk1 stability

et al. 2007

View full text Add to dashboard Cite

Here, we show that the human homologue of the Caenorhabditis elegans biological clock protein CLK-2 (HCLK2) associates with the S-phase checkpoint components ATR, ATRIP, claspin and Chk1. Consistent with a critical role in the S-phase checkpoint, HCLK2-depleted cells accumulate spontaneous DNA damage in S-phase, exhibit radio-resistant DNA synthesis, are impaired for damage-induced monoubiquitination of FANCD2 and fail to recruit FANCD2 and Rad51 (critical components of the Fanconi anaemia and homologous recombination pathways, respectively) to sites of replication stress. Although Thr 68 phosphorylation of the checkpoint effector kinase Chk2 remains intact in the absence of HCLK2, claspin phosphorylation and degradation of the checkpoint phosphatase Cdc25A are compromised following replication stress as a result of accelerated Chk1 degradation. ATR phosphorylation is known to both activate Chk1 and target it for proteolytic degradation, and depleting ATR or mutation of Chk1 at Ser 345 restored Chk1 protein levels in HCLK2-depleted cells. We conclude that HCLK2 promotes activation of the S-phase checkpoint and downstream repair responses by preventing unscheduled Chk1 degradation by the proteasome.The DNA damage response (DDR) is a complex process involving the orchestration of highly specialized cell-cycle checkpoints that need to be rapidly activated following the detection of damaged DNA. Each of these signalling cascades involves several unique and overlapping factors -classified as sensors, mediators, transducers and effectors -that ultimately lead to the spatio-temporal assembly of multi-protein complexes at the site of damage 1,2 . The functional importance of checkpoints in maintaining genome stability is highlighted by their conservation throughout eukaryotes. As such, defective checkpoint pathways in human cells leads to the accumulation of aberrant DNA and an increased risk of cancer progression, evident from the many human disease syndromes that result from defects in checkpoint factors 3,4 . Therefore, it is important to understand these complex mechanisms at the molecular level to further our knowledge of cancer progression and treatment.Checkpoints operate at the G1-S, S and G2-M boundaries of the cell cycle and are controlled by the ATM-Chk2 and ATR-Chk1 pathways. The S-phase checkpoint, which is under the control of the ATR-Chk1 pathway, has an essential role in maintaining replication-fork integrity during normal S-phase by preventing the collapse of stalled replication forks. The S-phase checkpoint also coordinates cell-cycle arrest and subsequent DNA-repair events when the replication fork encounters DNA damage 5,3,6 . Activation and recruitment of the Fanconi anaemia and homologous recombination-repair pathways to sites of replication stress requires an intact S-phase checkpoint 7 .Recent work in mouse models has highlighted a surprising, yet highly important link between biological clock proteins and the DDR 8,9 . It has been shown that two clock proteins, Per1 and Prd4, have integral roles...

show abstract

Section: Discussionmentioning

confidence: 99%

HCLK2 is essential for the mammalian S-phase checkpoint and impacts on Chk1 stability

et al. 2007

View full text Add to dashboard Cite

show abstract

“…This raises an apparent conundrum, because p12 degradation was dependent on ATR, which is associated with the intra-S-phase checkpoint. However, ATR activation by UV has been shown to take place in G1 cells [O'Driscoll et al, 2003]. The mechanism involves the generation of ssDNA and its coating by RPA as an essential step of nucleotide excision repair (NER), which leads to the recruitment of ATR and ATRinteracting protein (ATRIP) [Matsumoto et al, 2007;Vrouwe et al, 2011].…”

Section: Degradation Of P12 and The Conversion Of Pol D4 To Pol D3 Inmentioning

confidence: 99%

Regulation of human DNA polymerase delta in the cellular responses to DNA damage

Lee

Zhang

Lin

et al. 2012

Environ and Mol Mutagen

View full text Add to dashboard Cite

The p12 subunit of polymerase delta (Pol d) is degraded in response to DNA damage induced by UV, alkylating agents, oxidative, and replication stresses. This leads to the conversion of the Pol d4 holoenzyme to the heterotrimer, Pol d3. We review studies that establish that Pol d3 formation is an event that could have a major impact on cellular processes in genomic surveillance, DNA replication, and DNA repair. p12 degradation is dependent on the apical ataxia telangiectasia and Rad3 related (ATR) kinase and is mediated by the ubiquitin-proteasome system. Pol d3 exhibits properties of an ''antimutator'' polymerase, suggesting that it could contribute to an increased surveillance against mutagenesis, for example, when Pol d carries out bypass synthesis past small base lesions that engage in spurious base pairing. Chromatin immunoprecipitation analysis and examination of the spatiotemporal recruitment of Pol d to sites of DNA damage show that Pol d3 is the primary form of Pol d associated with cyclobutane pyrimidine dimer lesions and therefore should be considered as the operative form of Pol d engaged in DNA repair. We propose a model for the switching of Pol d with translesion polymerases, incorporating the salient features of the recently determined structure of monoubiquitinated proliferating cell nuclear antigen and emphasizing the role of Pol d3. Because of the critical role of Pol d activity in DNA replication and repair, the formation of Pol d3 in response to DNA damage opens the prospect that pleiotropic effects may ensue. This opens the horizons for future exploration of how this novel response to DNA damage contributes to genomic stability. Environ. Mol. Mutagen. 53:683-698, 2012. V V C 2012 Wiley Periodicals, Inc.

show abstract

“…The basis of Seckel syndrome remains largely undefined, many susceptibility loci have been identified, however, only one specific ATR hypomorphic mutation has been uncovered (O'Driscoll et al, 2003). Seckel syndrome is clinically characterised by dwarfism, abnormal brain development and microcephaly (Majewski and Goecke, 1982).…”

Section: Atr Activation In Response To Single Strand Dna Damagementioning

confidence: 99%

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

Smith¹,

Dejsuphong

Balestrini³

et al. 2009

Nat Cell Biol

View full text Add to dashboard Cite

The effects of ATM and ATR signalling induced by chromosomal breakage have been described extensively in modulating cell cycle progression up to the onset of mitosis.However, DNA damage checkpoint responses in mitotic cells are not well understood.This thesis reports on the effects of double strand breaks on the progression of mitosis.We found ATM and ATR activation can occur in mitotic Xenopus laevis egg extract and the induction of ATM and ATR by chromosomal breakages inhibits spindle assembly in both Xenopus egg extract and somatic cells. The delay in mitotic progression induced by ATM and ATR was found not to involve major spindle assembly factors activities such as, Cdk1, Plx1 and RCC1/Ran-GTP. However, normal anastral spindles formation around linear DNA coated beads, which can activate ATM and ATR, linked centrosome-driven spindle assembly to ATM and ATR dependent spindle defects. cDNA expression library screening was undertaken to identify novel ATM and ATR targets in this mitotic checkpoint pathway, through which the novel centrosomal protein XCEP63 was identified as a likely candidate. Data obtained from depletion and reconstitution of XCEP63 in Xenopus egg extract established that normal centrosome-driven spindle assembly requires XCEP63. Moreover, ATM and ATR phosphorylates XCEP63 on serine 560 and promotes delocalisation from the centrosome. ATM and ATR inhibition or addition of non-phosphorylable XCEP63 recombinant protein mutated at serine 560 prevents spindle assembly abnormalities.These findings suggest that ATM and ATR regulate mitotic events by targeting XCEP63 and centrosome-dependent spindle assembly. This pathway may provide support for DNA repair processes or regulate cell survival in the presence of mitotic DNA damage. 3

show abstract

A splicing mutation affecting expression of ataxia–telangiectasia and Rad3–related protein (ATR) results in Seckel syndrome

Cited by 710 publications

References 20 publications

HCLK2 is essential for the mammalian S-phase checkpoint and impacts on Chk1 stability

HCLK2 is essential for the mammalian S-phase checkpoint and impacts on Chk1 stability

Regulation of human DNA polymerase delta in the cellular responses to DNA damage

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

Contact Info

Product

Resources

About