ATRIP protects progenitor cells against DNA damagein vivo

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.

Progenitor death drives retinal dysplasia and neuronal degeneration in a mouse model of ATRIP-Seckel syndrome

“…TRP53-mediated cell-cycle arrest and apoptosis are common cellular responses to defective RSR and DSB ( Hafner et al, 2019 ). In both developing organs and adult organs, loss of the ATRIP-ATR complex in progenitor cells activates DDR, affecting progenitor cell survival and/or proliferation ( Lang et al, 2016 ; Lee et al, 2012 ; Matos-Rodrigues et al, 2020 preprint; Murga et al, 2009 ; Ruzankina et al, 2007 ). It has been shown that the ATR-Seckel mice have sustained replicative stress that results in TRP53 accumulation and neural progenitor cells apoptosis ( Murga et al, 2009 ).…”

“…Transgenic mice lines used in this work were as follows: α-Cre [Tg(Pax6-cre,GFP) 2Pgr ] ( Marquardt et al, 2001 ), Trp53 null (C3Ou.129S2 B6-TrTrp53 tm1Tyj/J ) ( Lowe et al, 1993 ), iRho-Cre ( Li et al, 2005 ) and Atrip Floxed (B6; Sv129- Atrip tm1.1pof ) ( Matos-Rodrigues et al, 2020 preprint). The mice were identified as follows: α -Cre +/− ; Atrip Flox/Flox = Atrip α-Cre ; α -Cre +/− ; Atrip Flox/Flox ; Trp53 −/− = Atrip DKO ; iRho-Cre +/− ; Atrip Flox/Flox = Atrip iRho-Cre .…”