FANCM-FAAP24 and HCLK2: roles in ATR signalling and the Fanconi anemia pathway.

The ATR signalling pathway coordinates the cellular response to replication stress, which is essential for the maintenance of genome integrity. HCLK2/Tel2 is a highly conserved orphan protein that binds directly to ATR and other PI3-kinase related kinases and plays a central role in checkpoint signalling responses.(1) Proteomic analyses of HCLK2 complexes confirmed ATR, ATRIP and DNA-PKcs as HCLK2 interacting factors and also uncovered two surprising interacting proteins, the heterodimeric Fanconi Anemia (FA) proteins FANCM and FAAP24. Our subsequent findings that ATR signalling is attenuated in FANCM and FAAP24-depleted cells, together with recent biochemical studies, suggested that remodelling of stalled replication forks by FANCM-FAAP24 is required to facilitate efficient activation of ATR signalling in response to replication stress.(2) Furthermore, our study revealed that the DNA translocase activity of FANCM is essential for efficient activation of the ATR signalling, a function that is separate and distinct from its role in targeting the FA core complex to sites of DNA damage. In this review we discuss the importance of these findings in the context of recent data and raise questions regarding the role of HCLK2 and FANCM-FAAP24 in human disease.