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RNA:DNA hybrids accumulate at DNA double-strand breaks (DSBs) and were shown to regulate homologous recombination repair. The mechanism responsible for the formation of these non-canonical RNA:DNA structures remains unclear although they were proposed to arise consequently to RNA polymerase II or III loading followed by DSB-induced de novo transcription at the break site. Here, we found no evidence of RNA polymerase recruitment at DSBs. Rather, strand-specific R-loop mapping revealed that RNA:DNA hybrids are mainly generated at DSBs occurring in transcribing loci, from the hybridization of pre-existing RNA to the 3′ overhang left by DNA end resection. We further identified the H3K4me3 reader spindlin 1 and the transcriptional regulator PAF1 as factors promoting RNA:DNA hybrid accumulation at DSBs, through their role in mediating transcriptional repression in cis to DSBs. Altogether, we provide evidence that RNA:DNA hybrids accumulate at DSBs occurring in transcribing loci as a result o

The persistence of post-replicative ssDNA gaps following PRIMPOL-mediated replication repriming is linked to chemosensitivity, and in all models reported to date the nuclease MRE11 has been implicated...

DNA double-strand breaks and unresolved DNA replication intermediates are particularly dangerous during mitosis. Paradoxically, cells inactivate canonical DNA repair mechanisms during chromosome segre...

Cell division requires strict control of DNA replication and centrosome duplication. Here, the authors reveal that DNA replication machinery transmits dual signals to control proper timing of centroso...

DNA replication stress is a driver of genome instability. Here, the authors identify a role of the E3 ligase RNF25 in promoting replication stress tolerance. Mechanistically, RNF25 recruits the fork p...

DNA damage tolerance is regulated by ubiquitination of PCNA. Here, the authors present kinetic and structural studies showing that USP1/UAF1 prefers trimming K63- and K48-ubiquitin chains down over cl...

Canal et al. used biochemical reconstitution of DNA replication to show that continued Okazaki fragment synthesis after nucleotide exhaustion depletes PCNA, RFC, and DNA polymerases ε and δ, deprotecting replication forks and impairing restart. By limiting Okazaki fragment generation and factor depletion, the replication checkpoint protects forks, allows restart, and promotes survival.

BCGB 2025, Birmingham Centre for Genome Biology Conference 2025

A position as Postdoctoral Research Associate is available at the Department of Cellular and Molecular Medicine, in the group headed by Dr. Andrew Blackford. Th

The replicative helicase CMG is targeted for removal or proteolysis by the E3 ubiquitin ligase TRAIP. This study describes how the de-ubiquitylating enzyme USP37 protects genome stability by preventin...

With detailed structural and molecular analyses, Longo et al. find that the BRCA2 C-terminal TR2, which is a critical cancer therapy resistance factor, reshapes the RAD51 dimer for B-DNA binding that is incompatible with double-strand break repair interactions but activates it in DNA replication fork protection.

Villa et al. show that the USP37 deubiquitylase is tethered to the CMG helicase at DNA replication forks in mammalian cells. USP37 protects cells during DNA replication stress by counteracting two replisome-coupled ubiquitin ligases. USP37 counteracts CUL2LRR1 during DNA synthesis defects and opposes TRAIP in response to topological stress.

ARID1A is a subunit of the BAF chromatin remodelling complex that is frequently mutated in cancer. It is challenging to predict how ARID1A loss impacts cancer therapy response because it participates ...

Scientific Reports - Parp1 deletion rescues cerebellar hypotrophy in xrcc1 mutant zebrafish

DNA double strand break repair pathways ensure genome stability and prevent disease. Here the authors show that the actin nucleating factor DIAPH1 and γ-actin promote homologous recombination (HR)-dep...

DNA double strand breaks (DSBs) are the effective lesion of cancer radiotherapy and induce gene editing. 53BP1 accumulates at DSBs and is implicated in end joining (EJ) repair, but its influence on DS...

The ubiquitin ligase, RNF168, promotes DNA break repair but must be regulated to prevent run-away ubiquitin signaling. Here, the authors identify a three-step post-translational cascade regulating RNF...

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