SummaryInterstrand cross-links (ICLs) are toxic DNA lesions interfering with DNA metabolism that are induced by widely used anticancer drugs. They have long been considered absolute roadblocks for replication forks, implicating complex DNA repair processes at stalled or converging replication forks. Recent evidence challenged this view, proposing that single forks traverse ICLs by yet elusive mechanisms. Combining ICL immunolabeling and single-molecule approaches in human cells, we now show that ICL induction leads to global replication fork slowing, involving forks not directly challenged by ICLs. Active fork slowing is linked to rapid recruitment of RAD51 to replicating chromatin and to RAD51/ZRANB3-mediated fork reversal. This global modulation of fork speed and architecture requires ATR activation, promotes single-fork ICL traverse—here, directly visualized by electron microscopy—and prevents chromosomal breakage by untimely ICL processing. We propose that global fork slowing by remodeling provides more time for template repair and promotes bypass of residual lesions, limiting fork-associated processing.

Chronic airflow limitation is the common denominator of patients with chronic obstructive pulmonary disease (COPD). However, it is not possible to predict morbidity and mortality of individual patients based on the degree of lung function impairment, nor does the degree of airflow limitation allow guidance regarding therapies. Over the last decades, understanding of the factors contributing to the heterogeneity of disease trajectories, clinical presentation, and response to existing therapies has greatly advanced. Indeed, diagnostic assessment and treatment algorithms for COPD have become more personalized. In addition to the pulmonary abnormalities and inhaler therapies, extra-pulmonary features and comorbidities have been studied and are considered essential components of comprehensive disease management, including lifestyle interventions. Despite these advances, predicting and/or modifying the course of the disease remains currently impossible, and selection of patients with a beneficial response to specific interventions is unsatisfactory. Consequently, non-response to pharmacologic and non-pharmacologic treatments is common, and many patients have refractory symptoms. Thus, there is an ongoing urgency for a more targeted and holistic management of the disease, incorporating the basic principles of P4 medicine (predictive, preventive, personalized, and participatory). This review describes the current status and unmet needs regarding personalized medicine for patients with COPD. Also, it proposes a systems medicine approach, integrating genetic, environmental, (micro)biological, and clinical factors in experimental and computational models in order to decipher the multilevel complexity of COPD. Ultimately, the acquired insights will enable the development of clinical decision support systems and advance personalized medicine for patients with COPD.

Chronic obstructive pulmonary disease (COPD) kills over three million people worldwide every year. Despite its high global impact, the knowledge about the underlying molecular mechanisms is still limited. In this study, we aimed to extend the available knowledge by identifying a small set of COPD-associated genes. We analysed different publicly available gene expression datasets containing whole lung tissue (WLT) and airway epithelium (AE) samples from over 400 human subjects for differentially expressed genes (DEGs). We reduced the resulting sets of 436 and 663 DEGs using a novel computational approach that utilises a random depth-first search to identify genes which improve the distinction between COPD patients and controls along the first principle component of the data. Our method identified small sets of 10 and 15 genes in the WLT and AE, respectively. These sets of genes significantly (p < 10–20) distinguish COPD patients from controls with high fidelity. The final sets revealed novel genes like cysteine rich protein 1 (CRIP1) or secretoglobin family 3A member 2 (SCGB3A2) that may underlie fundamental molecular mechanisms of COPD in these tissues.

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