Replication Stress-Induced DNA Damage in Renal Ciliopathies

RESEARCH HIGHLIGHTS Nature Reviews Nephrology 11, 632 (2015); published online 8 September 2015; doi:10.1038/nrneph.2015.151

CILIOPATHIES Replication stress-induced DNA damage in renal ciliopathies The association of nephronophthisis and increased levels of cyclin-dependent and related ciliopathies with mutations kinases (CDKs). Intervention with a CDK in ciliary proteins has been thought inhibitor rescued DNA damage, primary to indicate a pathogenic role for cilia cilia frequency, and centriole number in dysfunction in these diseases; however, kidney cells from Cep290-deficient mice. new findings show that DNA damage “CDK inhibitors have shown promising caused by replication stress might in fact results in renal cystic disease models but be the driving mechanism. “Our study no one knew why,” says Slaats. “Our study explored a commonly mutated ciliopathy provides the mechanism for this response gene at the base of the cilium, CEP290, and validates efficacy of CDK inhibition in and demonstrated that replication murine and human primary renal cells.” stress-induced DNA damage is the The researchers say their findings add common denominator for more general to the rationale that nuclear functions of renal ciliopathy phenotypes,” explain Circotasu/iStock/Thinkstock ciliopathy proteins participate in disease researchers Gisela Slaats and Rachel Giles. progression in renal cells and suggest that CEP290 is mutated in various damage response and the relevance of this further research should focus on the role ciliopathies, including nephronophthisis pathway to ciliopathy syndromes. of nuclear proteins. “It is time to start and Joubert syndrome. Although the The researchers found enhanced DNA looking beyond the cilium to understand protein can localize to the nucleus, as damage signalling in renal cells from a the cause of renal failure in patients with well as to the centrosomes and the base patient with CEP290-associated Joubert ciliopathies,” notes Giles. of the primary cilium, the function of syndrome, in kidneys from Cep290- Susan J. Allison nuclear CEP290 was unknown. Previous deficient mice, and in Cep290-deficient publications showing a potential link zebrafish embryos. Examination of between ciliopathy proteins and DNA primary kidney cells from Cep290- Original article Slaats, G. G. et al. DNA replication stress damage led Slaats and Giles to investigate deficient mice revealed increased numbers underlies renal phenotypes in CEP290-associated Joubert the role of CEP290 loss in the DNA of centrioles, evidence of replication stress syndrome. J. Clin. Invest. doi:10.1172/JCI80657