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

Author

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., and Giles, Rachel H.

Subjects
Joubert syndrome, DNA replication, Cellular proteins -- Physiological aspects -- Research, Health care industry
Abstract

Juvenile ciliopathy syndromes that are associated with renal cysts and premature renal failure are commonly the result of mutations in the gene encoding centrosomal protein CEP290. In addition to centrosomes and the transition zone at the base of the primary cilium, CEP290 also localizes to the nucleus; however, the nuclear function of CEP290 is unknown. Here, we demonstrate that reduction of cellular CEP290 in primary human and mouse kidney cells as well as in zebrafish embryos leads to enhanced DNA damage signaling and accumulation of DNA breaks ex vivo and in vivo. Compared with those from WT mice, primary kidney cells from Cep290-deficient mice exhibited supernumerary centrioles, decreased replication fork velocity, fork asymmetry, and increased levels of cyclin-dependent kinases (CDKs). Treatment of Cep290-deficient cells with CDK inhibitors rescued DNA damage and centriole number. Moreover, the loss of primary cilia that results from CEP290 dysfunction was rescued in 3D cell culture spheroids of primary murine kidney cells after exposure to CDK inhibitors. Together, our results provide a link between CEP290 and DNA replication stress and suggest CDK inhibition as a potential treatment strategy for a wide range of ciliopathy syndromes., Introduction Mutations in CEP290 are known to cause the entire spectrum of ciliopathies, including childhood renal failure due to nephronophthisis (NPHP) (1), Joubert syndrome (JS; MIM 610188), the lethal Meckel [...]

Published
2015
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3. Correction: Sherloc: a comprehensive refinement of the ACMG–AMP variant classification criteria

Author

Nykamp, Keith, primary, Anderson, Michael, additional, Powers, Martin, additional, Garcia, John, additional, Herrera, Blanca, additional, Ho, Yuan-Yuan, additional, Kobayashi, Yuya, additional, Patil, Nila, additional, Thusberg, Janita, additional, Westbrook, Marjorie, additional, Topper, Scott, additional, Aguilar, Sienna, additional, Aradhya, Swaroop, additional, Beltran, Daniel, additional, Bunker, Brandon, additional, Daly, Amy, additional, Deucher, Anne, additional, Ekstein, Tali, additional, Entezam, Ali, additional, Erhard, Karl, additional, Esplin, Ed, additional, Fulbright, Jennifer, additional, Fuller, Amy, additional, Gibson, Kristen McDonald, additional, Hambuch, Tina, additional, Harte, Rachel, additional, Hartshorne, Christy, additional, Haverfield, Eden, additional, Heidari, Nastaran, additional, Hogue, Michelle, additional, Iacoboni, Daniela, additional, Johnson, Britt, additional, Kang, Hio Chung, additional, Lewis, Rachel, additional, Martin, Shiloh, additional, McCalmon, Sarah, additional, Michalski, Scott, additional, Morgan, Cindy, additional, Murillo, Laura, additional, Nicolosi, Piper, additional, Ouyang, Karen, additional, Pardo, Carolina, additional, Quintana, Rita, additional, Rabideau, Marina, additional, Riethmaier, Darlene, additional, Stafford, Amanda, additional, Tahiliani, Jackie, additional, Tan, Chris, additional, Taylor, S. Paige, additional, Wang, Shu-Huei, additional, White, Hannah, additional, Wilson, Ian, additional, Winder, Tom, additional, and Zeman, Michelle K., additional

Published
2020
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10. Causes and consequences of replication stress.

Author

Zeman, Michelle K. and Cimprich, Karlene A.

Subjects
*GENETIC mutation, *NUCLEIC acids, *DNA, *BIOCHEMICAL genetics, *DNA damage
Abstract

Replication stress is a complex phenomenon that has serious implications for genome stability, cell survival and human disease. Generation of aberrant replication fork structures containing single-stranded DNA activates the replication stress response, primarily mediated by the kinase ATR (ATM- and Rad3-related). Along with its downstream effectors, ATR stabilizes and helps to restart stalled replication forks, avoiding the generation of DNA damage and genome instability. Understanding this response may be key to diagnosing and treating human diseases caused by defective responses to replication stress. [ABSTRACT FROM AUTHOR]

Published
2014
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