Defective ALC1 nucleosome remodeling confers PARPi sensitization and synthetic lethality with HRD.

Chromatin is a barrier to efficient DNA repair, as it hinders access and processing of certain DNA lesions. ALC1/CHD1L is a nucleosome-remodeling enzyme that responds to DNA damage, but its precise function in DNA repair remains unknown. Here we report that loss of ALC1 confers sensitivity to PARP inhibitors, methyl-methanesulfonate, and uracil misincorporation, which reflects the need to remodel nucleosomes following base excision by DNA glycosylases but prior to handover to APEX1. Using CRISPR screens, we establish that ALC1 loss is synthetic lethal with homologous recombination deficiency (HRD), which we attribute to chromosome instability caused by unrepaired DNA gaps at replication forks. In the absence of ALC1 or APEX1, incomplete processing of BER intermediates results in post-replicative DNA gaps and a critical dependence on HR for repair. Hence, targeting ALC1 alone or as a PARP inhibitor sensitizer could be employed to augment existing therapeutic strategies for HRD cancers.Work in I.A.’s group is funded by the WellcomeTrust (grant number 210634), BBSRC (BB/R007195/1), and Cancer ResearchUK (C35050/A22284). Work in D.A.’s group is funded by the Cancer ResearchUK Career Development Fellowship (grant number 16304). Work in the S.J.B.lab is supported by the Coun, which receives its core fundingfrom Cancer Research UK (FC0010048), the UK Medical Research Council(FC0010048), and the Wellcome Trust (FC0010048); a European Research Council (ERC) Advanced Investigator Grant (TelMetab); and Wellcome TrustSenior Investigator and Collaborative Grants. S.S.-B. was the recipient of an EMBO Long Term Fellowship (ALTF 707-2019) and a MSCA individual fellow-ship (grant 886577). Work in the J.R.C. group is funded by CRUK Career Devel-opment Fellowship (C52690/A19270) with infrastructural support from Well-come core award 090532/Z/09/ZS

Cochrane Airways reviews: can they make a difference?

Introduction: Cochrane reviews should inform and underpin decisions both about healthcare practice and delivery, and about topics for future primary research. Evaluation of the effectiveness and potential impact of reviews should address these two key issues. The 'lead time' between generation of good evidence of clinical and cost-effectiveness of healthcare interventions and its uptake in clinical practice can be long. It is thus unlikely that the impacts of Cochrane reviews on healthcare delivery and, especially outcomes, can yet be measured. However, it is possible to make projections about potential impacts using health economic modelling. It is also possible to identify the influence of reviews on selection of topics for new primary research commissioned by the UK NHS R&D Programme. Objective: (1) To determine the potential impact of a group of reviews about the management of asthma, which has hospital admission as a common outcome, on heath outcomes and healthcare COSB. (2) To determine the actual influence of a set of Cochrane Airways reviews on topics identified and prioritised for new commissioned primary research by the UK NHS R&D Programme. Methods: (1) Health economic modelling to determine potential impacts on health outcomes and healthcare costs. (2)Survey and analysis of commissioned UK NHS R&D Programmes. Results/Discussion: The results will be presented at the Colloquium in Octobe