Publications

Awwad SW, Serrano-Benitez A, Thomas JC, Gupta V and Jackson SP.

Nature Reviews Molecular Cell Biology 24, 477–494

All organisms possess molecular mechanisms that govern DNA repair and associated DNA damage response (DDR) processes. Owing to their relevance to human disease, most notably cancer, these mechanisms have been studied extensively, yet new DNA repair and/or DDR factors and functional interactions between them are still being uncovered. The emergence of CRISPR technologies and CRISPR-based genetic screens has enabled genome-scale analyses of gene-gene and gene-drug interactions, thereby providing new insights into cellular processes in distinct DDR-deficiency genetic backgrounds and conditions.

Morales-Juarez DA and Jackson SP.

NPJ Precision Oncology 6:85

The discovery of synthetic lethal interactions with genetic deficiencies in cancers has highlighted several candidate targets for drug development, with variable clinical success. Recent work has unveiled a promising synthetic lethal interaction between inactivation/ inhibition of the WRN DNA helicase and tumours with microsatellite instability, a phenotype that arises from DNA mismatch repair deficiency.

Sun D, Llora Batlle O, van den Ameele J, Thomas JC, He P, Lim K, Tang W, Xu C, Meyer KB, Teichmann SA, Marioni JC, Jackson SP, Brand AH, Rawlins EL.

EMBO J. 41:e111338

The balance between self-renewal and differentiation in human foetal lung epithelial progenitors controls the size and function of the adult organ. Moreover, progenitor cell gene regulation networks are employed by both regenerating and malignant lung cells, where modulators of their effects could potentially be of therapeutic value. Details of the molecular networks controlling human lung progenitor self-renewal remain unknown. We performed the first CRISPRi screen in primary human lung organoids to identify transcription factors controlling progenitor self-renewal.

Vincendeau E, Wei W, Zhang X, Planchais C, Yu W, Lenden-Hasse H, Cokelaer T, Pipoli da Fonseca J, Mouquet H, Adams DJ, Alt FW, Jackson SP, Balmus G, Lescale C, Deriano L.

Nat Commun. 13(1):3707.

SHLD1 is part of the Shieldin (SHLD) complex, which acts downstream of 53BP1 to counteract DNA double-strand break (DSB) end resection and promote DNA repair via non-homologous end-joining (NHEJ). While 53BP1 is essential for immunoglobulin heavy chain class switch recombination (CSR), long-range V(D)J recombination and repair of RAG-induced DSBs in XLF-deficient cells, the function of SHLD during these processes remains elusive. Here we report that SHLD1 is dispensable for lymphocyte development and RAG-mediated V(D)J recombination, even in the absence of XLF.

Cabello-Lobato MJ, Jenner M, Cisneros-Aguirre M, Brüninghoff K, Sandy Z, da Costa IC, Jowitt TA, Loch CM, Jackson SP, Wu Q, Mootz HD, Stark JM, Cliff MJ, Schmidt CK.

Nucleic Acids Res. 2022 Apr 14, Epub ahead of print

SUMOylation is critical for numerous cellular signalling pathways, including the maintenance of genome integrity via the repair of DNA double-strand breaks (DSBs). If misrepaired, DSBs can lead to cancer, neurodegeneration, immunodeficiency and premature ageing. Using systematic human proteome microarray screening combined with widely applicable carbene footprinting, genetic code expansion and high-resolution structural profiling, we define two non-conventional and topology-selective SUMO2-binding regions on XRCC4, a DNA repair protein important for DSB repair by non-homologous end-joining (NHEJ).

Franz A, Valledor P, Ubieto-Capella P, Pilger D, Galarreta A, Lafarga V, Fernández-Llorente A, de la Vega-Barranco G, den Brave F, Hoppe T, Fernandez-Capetillo O, Lecona E.

Cell Reports 37(2):109819.

The AAA+ ATPase VCP regulates the extraction of SUMO and ubiquitin-modified DNA replication factors from chromatin. We have previously described that active DNA synthesis is associated with a SUMO-high/ubiquitin-low environment governed by the deubiquitylase USP7. Here, we unveil a functional cooperation between USP7 and VCP in DNA replication, which is conserved from Caenorhabditis elegans to mammals.

LLoyd RL, Urban V, Muñoz-Martínez F, Ayestaran I, Thomas JC, de Renty C, O'Connor MJ, Forment JV, Galanty Y, Jackson SP.

Nucleic Acids Research 49 (15): 8665–8683

The protein kinase ATR plays pivotal roles in DNA repair, cell cycle checkpoint engagement and DNA replication. Consequently, ATR inhibitors (ATRi) are in clinical development for the treatment of cancers, including tumours harbouring mutations in the related kinase ATM. However, it still remains unclear which functions and pathways dominate long-term ATRi efficacy, and how these vary between clinically relevant genetic backgrounds.

Carnie C and Jackson SP

Nature Cell Biology 23, 584-586

Transcription-coupled repair of DNA lesions takes place across all domains of life. A transcription-elongation factor, ELOF1, highly conserved in eukaryotes, has now been shown to play a key role in this process. Importantly, these findings also include evidence of a second transcription-coupled repair pathway in mammalian cells.

News & Views on “Elongation factor ELOF1 drives transcription-coupled repair and prevents genome instability”, Geijer et al, and “ELOF1 is a transcription-coupled DNA repair factor that directs RNA polymerase II ubiquitylation”, van Der Weegen Y et al.