The PIN1-p38-CtIP signalling axis protects stalled replication forks from deleterious degradation.

Human CtIP plays a critical role in homologous recombination (HR) by promoting the resection of DNA double-strand breaks. Moreover, CtIP maintains genome stability through protecting stalled replication forks from nucleolytic degradation. However, the upstream signalling mechanisms governing the molecular switch between these two CtIP-dependent processes remain largely elusive.

Cancer-cell-derived cGAMP limits the activity of tumor-associated CD8 T cells.

Using a mouse tumor model with inducible cancer-cell-intrinsic cyclic GMP-AMP (cGAMP) synthase (cGAS) expression, we show that cancer-cell-derived cGAMP is essential and sufficient to trigger a sustained type I interferon response within the tumor microenvironment. This leads to improved CD8 T cell-dependent tumor restriction. However, cGAMP limits the proliferation, survival, and function of stimulator of IFN genes (STING)-expressing, but not of STING-deficient, CD8 T cells.

H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours.

Histone H2AX plays a key role in DNA damage signalling in the surrounding regions of DNA double-strand breaks (DSBs). In response to DNA damage, H2AX becomes phosphorylated on serine residue 139 (known as γH2AX), resulting in the recruitment of the DNA repair effectors 53BP1 and BRCA1. Here, by studying resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2-deficient mammary tumours, we identify a function for γH2AX in orchestrating drug-induced replication fork degradation.

PLK1 regulates CtIP and DNA2 interplay in long-range DNA end resection.

DNA double-strand break (DSB) repair is initiated by DNA end resection. CtIP acts in short-range resection to stimulate MRE11-RAD50-NBS1 (MRN) to endonucleolytically cleave 5'-terminated DNA to bypass protein blocks. CtIP also promotes the DNA2 helicase-nuclease to accelerate long-range resection downstream from MRN.