Abstract
The maintenance of genomic stability during the cell cycle of progenitor cells is essential for the faithful transmission of genetic information. Mutations in genes that ensure genome stability lead to human developmental syndromes. Mutations in Ataxia Telangiectasia and Rad3-related (ATR) or in ATR-interacting protein (ATRIP) lead to Seckel syndrome, which is characterized by developmental malformations and short life expectancy. While the roles of ATR in replicative stress response and chromosomal segregation are well established, it is unknown how ATRIP contributes to maintaining genomic stability in progenitor cells in vivo. Here, we generated the first mouse model to investigate ATRIP function. Conditional inactivation of Atrip in progenitor cells of the CNS and eye led to microcephaly, microphthalmia and postnatal lethality. To understand the mechanisms underlying these malformations, we used lens progenitor cells as a model and found that ATRIP loss promotes replicative stress and TP53-dependent cell death. Trp53 inactivation in Atrip-deficient progenitor cells rescued apoptosis, but increased mitotic DNA damage and mitotic defects. Our findings demonstrate an essential role of ATRIP in preventing DNA damage accumulation during unchallenged replication.
Highlights
Genomic stability is crucial for cellular and tissue homeostasis, normal development, and the prevention of tumorigenesis and aging
To understand the function of ATR-interacting protein (ATRIP) in vivo, we focused our analysis on lens development, because this tissue is formed by only one type of progenitor cell with well-characterized cell cycle progression
No change in the proportion of mitotic cells, as revealed by phospho-histone H3 staining, was observed in Atrip-deficient progenitors (Fig. 3f). These findings suggest that the ATRIP-ATR signaling pathway is key to preventing DNA damage accumulation and apoptosis in progenitor cells
Summary
Genomic stability is crucial for cellular and tissue homeostasis, normal development, and the prevention of tumorigenesis and aging. Mutations in genes that ensure genome stability and proper chromosomal segregation lead to human developmental syndromes[1,2]. DNA damage response (DDR) pathways sense, signal and repair different types of DNA damage and are crucial for maintaining genomic stability[3]. The Ataxia Telangiectasia and Rad3related (ATR) kinase regulates replication fork firing and stability to ensure the proper timing of DNA replication during S-phase and cell cycle checkpoints to prevent mitosis in cells with under-replicated DNA4,5. ATR-interacting protein (ATRIP) and activates ATR, which coordinates a replicative stress response (RSR)[6,7]. ATR protein stability and activity as well as all the described functions of ATR depend on ATRIP6,8
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