Nephronophthisis-related ciliopathies (NPHP-RC) are degenerative recessive diseases that affect kidney, retina, and brain. Genetic defects in NPHP gene products that localize to cilia and centrosomes defined them as "ciliopathies.” However, disease mechanisms remain poorly understood. Here, we identify by whole-exome resequencing, mutations of MRE11, ZNF423, and CEP164 as causing NPHP-RC. All three genes function within the DNA damage response (DDR) pathway. We demonstrate that, upon induced DNA damage, the NPHP-RC proteins ZNF423, CEP164, and NPHP10 colocalize to nuclear foci positive for TIP60, known to activate ATM at sites of DNA damage. We show that knockdown of CEP164 or ZNF423 causes sensitivity to DNA damaging agents and that cep164 knockdown in zebrafish results in dysregulated DDR and an NPHP-RC phenotype. Our findings link degenerative diseases of the kidney and retina, disorders of increasing prevalence, to mechanisms of DDR. Display omitted Display omitted ► Mutations of ZNF423 or CEP164 are causes of retinal-renal ciliopathies ► The gene products colocalize with TIP60 at both centrosomes and nuclear foci ► Knockdown of ZNF423 or CEP164 impairs DNA damage response signaling ► Knockdown of cep164 in zebrafish causes a ciliopathy phenotype and dysregulated DDR Whole-exome resequencing of individuals with ciliopathies reveals mutations in genes that are involved in DNA damage response signaling, providing new insight into the pathogenic mechanisms behind this class of degenerative disorders.