Pauline C. Conroy

Ollscoil na Gaillimhe – University of Galway

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Ciaran G. Morrison

Ollscoil na Gaillimhe – University of Galway

Peter Dockery

Ollscoil na Gaillimhe – University of Galway

Pierce Lalor

Ollscoil na Gaillimhe – University of Galway

Michelle M. Le Beau

University of Chicago

Chiara Saladino

Almac (United Kingdom)

Damien Reynaud

Cincinnati Children's Hospital Medical Center

Emmanuelle Passegué

University of California, San Francisco

Sietske T. Bakker

Broad Center

Tiago J. Dantas

Universidade do Porto

Johanna Flach

University Medical Centre Mannheim

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University of California, San Francisco

Ollscoil na Gaillimhe – University of Galway

Broad Center

UCSF Helen Diller Family Comprehensive Cancer Center

Columbia University

Columbia University Irving Medical Center

University of Konstanz

German Cancer Research Center

Heidelberg University

University of Wisconsin–Madison

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Centriolar and ciliary responses to DNA damage

Pauline C. Conroy

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Increased γH2AX Foci in Old Hematopoietic Stem Cells Are Independent of the DNA Damage Response and Linked to Inefficient DNA Replication/Transcription

Blood (2012)

Johanna Flach Sietske T. Bakker Pauline C. Conroy Damien Reynaud Michelle M. Le Beau

PARP1

10.1182/blood.v120.21.1207.1207

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Centriole separation in DNA damage‐induced centrosome amplification

Environmental and Molecular Mutagenesis (2009)

Chiara Saladino Emer Bourke Pauline C. Conroy Ciaran G. Morrison

Abstract Altered centrosome numbers are seen in tumor cells in response to DNA damaging treatments and are hypothesised to contribute to cancer development. The mechanism by which the centrosome and chromosome cycles become disconnected after DNA damage is not yet clear. Here, we show that centrosome amplification occurs after ionising radiation (IR) in chicken DT40 cells that lack DNA‐PK, Ku70, H2AX, Xpa, and Scc1, demonstrating that these activities are not required for centrosome amplification. We show that inhibition of topoisomerase II induces Chk1‐dependent centrosome amplification, a similar response to that seen after IR. In the immortalised, nontransformed hTERT‐RPE1 line, we observed centriole splitting, followed by dose‐dependent centrosome amplification, after IR. We found that IR results in the formation of single, not multiple, daughter centrioles during centrosome amplification in U2OS osteosarcoma cells. Analysis of BRCA1 and BRCA2 mutant tumor cells showed high levels of centriole splitting in the absence of any treatment. IR caused pronounced levels of centrosome amplification in BRCA1 mutant breast cancer cells. These data show that centrosome amplification occurs after different forms of DNA damage in chicken cells, in nontransformed human cells and in human tumor cell lines, indicating that this is a general response to DNA damaging treatments. Together, our data suggest that centriole splitting is a key step in potentiation of the centrosome amplification that is a general response to DNA damage. Environ. Mol. Mutagen. 2009. © 2009 Wiley‐Liss, Inc.

Centriole

Centrosome cycle

Ku70

10.1002/em.20477

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Citations (39)

Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells

Nature (2014)

Johanna Flach Sietske T. Bakker Mary Mohrin Pauline C. Conroy Eric M. Pietras

10.1038/nature13619

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Calcium-Binding Capacity of Centrin2 Is Required for Linear POC5 Assembly but Not for Nucleotide Excision Repair

PLoS ONE (2013)

Tiago J. Dantas Owen Daly Pauline C. Conroy Martin Tomáš Yifan Wang

Centrosomes, the principal microtubule-organising centres in animal cells, contain centrins, small, conserved calcium-binding proteins unique to eukaryotes. Centrin2 binds to xeroderma pigmentosum group C protein (XPC), stabilising it, and its presence slightly increases nucleotide excision repair (NER) activity in vitro. In previous work, we deleted all three centrin isoforms present in chicken DT40 cells and observed delayed repair of UV-induced DNA lesions, but no centrosome abnormalities. Here, we explore how centrin2 controls NER. In the centrin null cells, we expressed centrin2 mutants that cannot bind calcium or that lack sites for phosphorylation by regulatory kinases. Expression of any of these mutants restored the UV sensitivity of centrin null cells to normal as effectively as expression of wild-type centrin. However, calcium-binding-deficient and T118A mutants showed greatly compromised localisation to centrosomes. XPC recruitment to laser-induced UV-like lesions was only slightly slower in centrin-deficient cells than in controls, and levels of XPC and its partner HRAD23B were unaffected by centrin deficiency. Interestingly, we found that overexpression of the centrin interactor POC5 leads to the assembly of linear, centrin-dependent structures that recruit other centrosomal proteins such as PCM-1 and NEDD1. Together, these observations suggest that assembly of centrins into complex structures requires calcium binding capacity, but that such assembly is not required for centrin activity in NER.

10.1371/journal.pone.0068487

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C-NAP1 and rootletin restrain DNA damage-induced centriole splitting and facilitate ciliogenesis

Cell Cycle (2012)

Pauline C. Conroy Chiara Saladino Tiago J. Dantas Pierce Lalor Peter Dockery

Cilia are found on most human cells and exist as motile cilia or non-motile primary cilia. Primary cilia play sensory roles in transducing various extracellular signals, and defective ciliary functions are involved in a wide range of human diseases. Centrosomes are the principal microtubule-organizing centers of animal cells and contain two centrioles. We observed that DNA damage causes centriole splitting in non-transformed human cells, with isolated centrioles carrying the mother centriole markers CEP170 and ninein but not kizuna or cenexin. Loss of centriole cohesion through siRNA depletion of C-NAP1 or rootletin increased radiation-induced centriole splitting, with C-NAP1-depleted isolated centrioles losing mother markers. As the mother centriole forms the basal body in primary cilia, we tested whether centriole splitting affected ciliogenesis. While irradiated cells formed apparently normal primary cilia, most cilia arose from centriolar clusters, not from isolated centrioles. Furthermore, C-NAP1 or rootletin knockdown reduced primary cilium formation. Therefore, the centriole cohesion apparatus at the proximal end of centrioles may provide a target that can affect primary cilium formation as part of the DNA damage response.

Ciliogenesis

Centriole

Basal body

Motile cilium

10.4161/cc.21986

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Citations (42)