Cyclin-dependent kinases (CDKs) coordinate cell cycle checkpoints with DNA repair mechanisms that together maintain genome stability. However, the myriad mechanisms that can give rise to genome instability are still to be fully elucidated. Here, we identify CDK18 (PCTAIRE 3) as a novel regulator of genome stability, and show that depletion of CDK18 causes an increase in endogenous DNA damage and chromosomal abnormalities. CDK18-depleted cells accumulate in early S-phase, exhibiting retarded replication fork kinetics and reduced ATR kinase signaling in response to replication stress. Mechanistically, CDK18 interacts with RAD9, RAD17 and TOPBP1, and CDK18-deficiency results in a decrease in both RAD17 and RAD9 chromatin retention in response to replication stress. Importantly, we demonstrate that these phenotypes are rescued by exogenous CDK18 in a kinase-dependent manner. Collectively, these data reveal a rate-limiting role for CDK18 in replication stress signalling and establish it as a novel regulator of genome integrity.

RECQL5 is a member of the RecQ family of DNA helicases and has key roles in homologous recombination, base excision repair, replication and transcription. The clinicopathological significance of RECQL5 expression in breast cancer is unknown. In this study, we have evaluated RECQL5 mRNA expression in 1977 breast cancers, and RECQL5 protein level in 1902 breast cancers [Nottingham Tenovus series (n = 1650) and ER- cohort (n = 252)]. Expression levels were correlated to aggressive phenotypes and survival outcomes. High RECQL5 mRNA expression was significantly associated with high histological grade (P = 0.007), HER2 overexpression (P = 0.032), ER+/HER2-/high proliferation genefu subtype (P < 0.0001), integrative molecular clusters (intClust 1and 9) (P < 0.0001) and poor survival (P < 0.0001). In subgroup analysis, high RECQL5 mRNA level remains significantly associated with poor BCSS in ER+ cohort (P < 0.0001) but not in ER- cohort (P = 0.116). At the protein level, in tumours with low RAD51, high RECQL5 level was significantly associated with high histological grade (P < 0.0001), higher mitotic index (P = 0.008), dedifferentiation (P = 0.025), pleomorphism (P = 0.027) and poor survival (P = 0.003). In subgroup analysis, high RECQL5/low RAD51 remains significantly associated with poor BCSS in ER+ cohort (P = 0.010), but not in ER- cohort (P = 0.628). In multivariate analysis, high RECQL5 mRNA and high RECQL5/low RAD51 nuclear protein coexpression independently influenced survival (P = 0.022) in whole cohort and in the ER+ subgroup. Preclinically, we show that exogenous expression of RECQL5 in MCF10A cells can drive proliferation supporting an oncogenic function for RECQL5 in breast cancer. We conclude that RECQL5 is a promising biomarker in breast cancer.

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Combination treatment with pegylated interferon (Peg-IFN) and ribavirin remains the gold standard in the treatment of chronic hepatitis C. This therapy is limited by many side-effects including anaemia, neutropenia and reduced quality of life. The use of adjuvant agents to reduce the frequency of dose reductions because of haematological side-effects has been proven to be effective but there are few reports of what effect the use of these adjuvant therapies is having on sustained virological response (SVR). The aim of the study was to assess the clinical impact on sustained virological response of adjuvant therapies during combination therapy with Peg-IFN and ribavirin for chronic hepatitis C. A total of 132 patients, 96 males, were included in the study. The overall SVR was 66.7%, with 50% of genotype 1/4/6 (n = 27/54) patients achieving SVR and 78.2% of genotypes 2/3. The overall SVR of the treatment naïve patients (83/121) was 68.6%. Fifty-one of these patients were genotype 1 with 49.0% (25/51) of this group achieving SVR. The genotype 2/3 group of treatment naïve patients reached an SVR of 82.9% (58/70). Adjuvant therapy was used in 57 patients (43.8%). With the use of supportive adjuvant therapy, we achieved an overall SVR of 66.7% and in treatment naïve patients 68.6%. In genotype 1 patients, SVR rates of up to 46% have been reported in previous studies without the use of erythropoietin and granulocyte colony stimulating factor. We have demonstrated the SVR for genotype 1 can be improved to 50% overall.