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ATR and CHK1 play key roles in the protection and recovery of the stalled replication forks. Claspin, an adaptor for CHK1 activation, is essential for DNA damage signaling and efficient replication fork progression. Here, we show that tristetraprolin (TTP), an mRNA-binding protein, can modulate the replication stress response via stabilization of ClaspinmRNA. TTPdepletion compromised specifically in the phosphorylation of CHK1, but not p53 or H2AX among other ATR substrates, and produced CHK1-defective replication phenotypes including accumulation of stalled replication forks. Importantly, the expression of siRNA–resistant TTPin TTP-deficient cells restored CHK1 phosphorylation and reduced the number of stalled replication forks as close to the control cells. Besides, we found that TTP was required for efficient replication fork progression even in the absence of exogenous DNA damage in a Claspin-dependent manner. Mechanistically, TTP was able to bind to the 3′-untranslated region of ClaspinmRNA to increase the stability of ClaspinmRNA which eventually contributed to the subsequent ATR–CHK1 activation upon DNA damage. Taken together, our results revealed an intimate link between TTP-dependent ClaspinmRNA stability and ATR–CHK1-dependent replication fork stability to maintain replication fork integrity and chromosomal stability.

Vaccinia-related kinase 1 (VRK1) is a histone kinase that phosphorylates histone H3 at Thr-3 and Ser-10. This study shows that mitogen-activated protein kinase phosphatase 2 regulates this phosphorylation negatively via interaction with VRK1, regardless of VRK1’s phosphatase activity.

The mammalian circadian system synchronizes organisms’ daily cyclical physiology from gene expression to gross behavioral patterns. A new study from our group suggests that DNA repair is also intimately linked to circadian rhythm. Since the repair of DNA lesions contributes to the resistance of chemotherapy with DNA damaging agents such as cisplatin, understanding the fundamental molecular mechanism regulating DNA repair pathways is important for cancer therapy. Here we review the significance of the connection linking the circadian clock with nucleotide excision repair and discuss potential implications for chemotherapy.