The accumulation of DNA damage can have important consequences that limit the lifespan of mammalian organisms such as ageing or cancer. On one hand, one of the current theories of ageing is based on the accumulation of DNA damage1
. Accordingly, signals of an activated DDR have been shown to increase on aged tissues and stem cells (SC)2,3
, and a number of murine models with impaired DNA repair show features of premature ageing4
. On the other hand, damaged DNA is the source of the mutations that drive malignant transformation. Therefore, it is not surprising that organisms have evolved complex signalling pathways to protect their DNA. In particular, the so-called DNA damage response (DDR) starts with the activation of either one of two members of the PIKK family of protein kinases: Ataxia Telangiectasia Mutated (ATM) and ATM and Rad3-related (ATR)5
. Whereas ATM is activated by DNA double strand breaks (DSBs), ATR responds to ssDNA both at resected DSBs as well as at aberrant replicative structures that compromise genome integrity during S phase. Regardless of the kinase that initiates the signalling, the final outcome of the DDR is to promote DNA repair while it delays cell cycle progression until chromosomes are healed.
Whereas ATM deficient animals were generated more than a decade ago6-8
, deciphering the physiological roles of ATR has been hampered by the essential nature of this kinase9,10
. However, although complete elimination of Atr
is incompatible with life, a seminal study found a hypomorphic mutation in human patients of a rare human disease known as the Seckel Syndrome (SS) (OMIM 210600)11
. This disease was first described by Helmut Seckel in 1960 as “bird-headed dwarfism” because of the severe dwarfism and craniofacial features of the patients12
. In homozygosity, the mutation brings ATR to almost undetectable levels due to a splicing defect, but yet the protein that is left is sufficient to sustain life. We have here exploited the human Atr
-Seckel mutation to generate a viable model for the study of ATR function in mammals.