Axel Behrens

Role of ATMIN in cancer

The checkpoint kinase ATM (ataxia telangiectasia mutated) transduces genomic stress signals to halt cell cycle progression and promote DNA repair in response to DNA damage¹.

In the early stages of cancer development, the initial tumour cell experiences 'oncogenic stress', which evokes an intrinsic cellular reaction that aims to eliminate pre-cancerous cells. This barrier against tumour formation is thought to involve oncogene-induced senescence and is associated with signs of DNA replication stress. The DNA damage response (DDR) plays a crucial role in this form a tumour defense since mutations compromising this checkpoint, including defects in the ATM-Chk2-p53 pathway, allow cell proliferation, survival, increased genomic instability and tumour progression^{2, 3}.

We have recently identified a novel essential cofactor for ATM, ATMIN (ATM interacting protein). Several observations suggested that ATMIN plays a key role in ATM signalling. ATMIN and ATM protein stability were mutually dependent, indicative of intimate physical interaction. Moreover, ATMIN bound ATM and controlled ATM activity in a stimulus-dependent fashion⁴.

While ATMIN appears to be a key regulator of ATM, its role in the ATM-dependent cellular defense to cancer is unclear. A combination of biochemical approaches and advanced mouse genetics, using conditional mouse mutants for ATMIN, will be employed to elucidate ATMIN function in cancer.

References

1. Shiloh Y. ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer 2003; 3: 155-168.
2. Di Micco R, et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 2006; 444: 638-642.
3. Bartkova J, et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 2006; 444: 633-637.
4. Kanu N and Behrens A. ATMIN defines an NBS1-independent pathway of ATM signalling. EMBO J 2007; 26: 2933-2941.