USP49 is a novel deubiquitylating enzyme for γ H2AX in DNA double-strand break repair.

DNA double-strand break (DSB) that is one of the most serious DNA lesions is mainly repaired by two mutually exclusive pathways, homologous recombination and non-homologous end-joining. Proper choice of DSB repair pathway, in which recruitment of 53BP1 to chromatin around DSB sites plays a pivotal role, is crucial for maintaining genome integrity. Ubiquitylations of histone H2A and H2AX on Lys15 are prerequisite for 53BP1 loading onto chromatin.

USP42 enhances homologous recombination repair by promoting R-loop resolution with a DNA-RNA helicase DHX9.

The nucleus of mammalian cells is compartmentalized by nuclear bodies such as nuclear speckles, however, involvement of nuclear bodies, especially nuclear speckles, in DNA repair has not been actively investigated. Here, our focused screen for nuclear speckle factors involved in homologous recombination (HR), which is a faithful DNA double-strand break (DSB) repair mechanism, identified transcription-related nuclear speckle factors as potential HR regulators. Among the top hits, we provide evidence showing that USP42, which is a hitherto unidentified nuclear speckles protein, promotes HR by facilitating BRCA1 recruitment to DSB sites and DNA-end resection.