DNA replication stress underlies renal phenotypes in CEP290-associated Joubert syndrome

Slaats, Gisela G.; Saldivar, Joshua C.; Bacal, Julien; Zeman, Michelle K.; Kile, Andrew C.; Hynes, Ann Marie; Srivastava, Shalabh; Nazmutdinova, Jekaterina; Ouden, Krista den; Zagers, Miriam S.; Foletto, Veronica; Verhaar, Marianne C.; Miles, Colin; Sayer, John A.; Cimprich, Karlene A.; Giles, Rachel

doi:10.1172/jci80657

Cited by 47 publications

(56 citation statements)

References 33 publications

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“…The exact mechanism by which senescence is evoked in Glis2 null cells is still unclear, but the abnormal activation of Chk1 that we have observed, is suggestive that replicative stress during the S phase of the cell cycle may be the primary cause of senescence in these cells. 37 Interestingly, other ciliary proteins associated with ciliopathy phenotypes have recently been shown to be required for correct activation and functioning of the pathways that control the cellular response to DNA damage, 10-12,38-41 suggesting that permanent cell cycle arrest and senescence could be a common feature of these diseases. In this regard, it is worth noticing that expression of many secreted factors (extracellular matrix proteases, matrix components, chemokines, and cytokines), recognized as part of the senescence secretory–associated phenotype 42 are upregulated in Glis2 null kidneys.…”

Section: Discussionmentioning

confidence: 99%

Loss of Glis2/NPHP7 causes kidney epithelial cell senescence and suppresses cyst growth in the Kif3a mouse model of cystic kidney disease

Rauhauser

et al. 2016

Kidney International

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Enlargement of kidney tubules is a common feature of multiple cystic kidney diseases in humans and mice. However, while some of these pathologies are characterized by cyst expansion and organ enlargement, in others, progressive interstitial fibrosis and kidney atrophy prevail. The Kif3a knockout mouse is an established non-orthologous mouse model of cystic kidney disease. Conditional inactivation of Kif3a in kidney tubular cells results in loss of primary cilia and rapid cyst growth. Conversely, loss of function of the gene GLIS2/NPHP7 causes progressive kidney atrophy, interstitial inflammatory infiltration, and fibrosis. Kif3a null tubular cells have unrestrained proliferation and reduced stabilization of p53 resulting in a loss of cell cycle arrest in the presence of DNA damage. In contrast, loss of Glis2 is associated with activation of checkpoint kinase 1, stabilization of p53, and induction of cell senescence. Interestingly, the cystic phenotype of Kif3a knockout mice is partially rescued by genetic ablation of Glis2 and pharmacological stabilization of p53. Thus, Kif3a is required for cell cycle regulation and the DNA damage response, whereas cell senescence is significantly enhanced in Glis2 null cells. Hence, cell senescence is a central feature in nephronophthisis type 7 and Kif3a is unexpectedly required for efficient DNA damage response and cell cycle arrest.

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Section: Discussionmentioning

confidence: 99%

Loss of Glis2/NPHP7 causes kidney epithelial cell senescence and suppresses cyst growth in the Kif3a mouse model of cystic kidney disease

Rauhauser

et al. 2016

Kidney International

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“…ciliopathy (NPHP-RC) genes identified pathogenic variants in several DNA repair and DDRsignalling proteins including FAN1, MRE11, CEP164 and ZNF432 (76,77). Conversely, reduced expression of multiple NPHP-RC genes has been shown to induce replication stress, S phase accumulation and elevated levels of DNA damage in several model systems (78)(79)(80)(81)(82).…”

Section: Ofd Type I Lcls Exhibit a Hypersensitive Dsb-induced G2-m Chmentioning

confidence: 99%

Oral-facial-digital syndrome type I cells exhibit impaired DNA repair; unanticipated consequences of defective OFD1 outside of the cilia network

Carpenter

Alfieri

et al. 2016

Hum. Mol. Genet.

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“…Rachel Giles (University Medical Center Utrecht) demonstrated that loss of CEP290 in mouse kidneys and cells increased DNA damage signaling, DNA replication stress and cyclin-dependent kinase (CDK) activity. Importantly, treatment of Cep290 -deficient cells with CDK1/2 inhibitors rescued the DNA damage as well as the loss of primary cilia (Slaats et al , 2015). Brad Yoder (University of Alabama) presented in vivo imaging of renal cilia, using the CiliaGFP mouse, which globally expresses a SSTR3:GFP fusion protein causing cilia to fluoresce (O’Connor et al , 2013).…”

Section: Cilia In Sickness and In Healthmentioning

confidence: 99%

An age of enlightenment for cilia: The FASEB summer research conference on the “Biology of Cilia and Flagella”

Tran

Lechtreck

2016

Developmental Biology

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From July 19–24, 2015, 169 clinicians and basic scientists gathered in the vertiginous heights of Snowmass, Colorado (2,502 m) for the fourth FASEB summer research conference on the ‘Biology of Cilia and Flagella’. Organizers Maureen Barr (Rutgers University), Iain Drummond (Massachusetts General Hospital/Harvard Medical School), and Jagesh Shah (Brigham and Women’s Hospital/Harvard Medical School) assembled a program filled with new data and forward-thinking ideas documenting the ongoing growth of the field. Sixty oral presentations and 77 posters covered novel aspects of cilia structure, ciliogenesis, cilia motility, cilia-mediated signaling, and cilia-related disease. In this report, we summarize the meeting, highlight exciting developments and discuss open questions.

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DNA replication stress underlies renal phenotypes in CEP290-associated Joubert syndrome

Cited by 47 publications

References 33 publications

Loss of Glis2/NPHP7 causes kidney epithelial cell senescence and suppresses cyst growth in the Kif3a mouse model of cystic kidney disease

Loss of Glis2/NPHP7 causes kidney epithelial cell senescence and suppresses cyst growth in the Kif3a mouse model of cystic kidney disease

Oral-facial-digital syndrome type I cells exhibit impaired DNA repair; unanticipated consequences of defective OFD1 outside of the cilia network

An age of enlightenment for cilia: The FASEB summer research conference on the “Biology of Cilia and Flagella”

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