ATR localizes to the photoreceptor connecting cilium and deficiency leads to severe photoreceptor degeneration in mice

Abstract

Ataxia-telangiectasia and Rad3 (ATR), a sensor of DNA damage, is associated with the regulation and control of cell division. ATR deficit is known to cause Seckel syndrome, characterized by severe proportionate short stature and microcephaly. We used a mouse model for Seckel disease to study the effect of ATR deficit on retinal development and function and we have found a new role for ATR, which is critical for the postnatal development of the photoreceptor (PR) layer in mouse retina. The structural and functional characterization of the ATR(+/s) mouse retinas displayed a specific, severe and early degeneration of rod and cone cells resembling some characteristics of human retinal degenerations. A new localization of ATR in the cilia of PRs and the fact that mutant mice have shorter cilia suggests that the PR degeneration here described results from a ciliary defect.

The leukemia-associated Rho guanine nucleotide exchange factor LARG is required for efficient replication stress signaling

“…[37][38][39][40][41] Pertinent to the work presented here, is the finding that ATR localizes to the photoreceptor connecting cilium. 39 Consistent with a putative functional role for ATR at the cilia, ATR-deficient mice exhibit ciliary defects and photoreceptor degeneration. 39 Furthermore, it has been recently demonstrated that the renal ciliopathyassociated kinase Nek8 also facilitates ATR signaling as part of the cellular responses to replication stress to help preserve genomic integrity.…”

The role of primary cilia in the development and disease of the retina

“…231 ATR is a DNA damage sensor, potentially extending the role of photoreceptors, and primary cilia in general, to involvement in the DNA damage response (DDR). Supporting this hypothesis, mutations in other DDR genes (CEP164 and ZNF423) have been found in ciliopathy patients with retinal degeneration.…”

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

“…CEP290 is a large multidomain centrosomal protein (6); identified binding partners of CEP290 include centrosomal proteins CEP131 and CCDC13; scaffold proteins pericentrin and PCM1; transcription factors, including ATF4; and proteins that are implicated in the DNA damage response (DDR), for example, ataxia telangiectasia and RAD3-related (ATR) (1,(7)(8)(9). The localization of CEP290 to the centrosome is dynamic, depending on the stage of cell cycle and expression of the primary cilium (1).…”