Fig. 6

Model of USP48 function in restricting extended DNA end resection. a USP48 cleaves the C-terminal ubiquitin modification of H2A, limiting the extent of SMARCAD1 nucleosome remodeling and 53BP1 positioning. 53BP1 in turn restrains DNA end processing and consequently direct repeats are rarely exposed either side of the DSB, favoring GC (one side of the break is illustrated). Without USP48 activity, H2A modification is unopposed and SMARCAD1 nucleosome remodeling is extended further from the break, resulting in 53BP1 positioning further from the break site. 53BP1 is unable to constrain extended resection, resulting in increased GC, and, as repeats either side of the break are more often exposed, SSA is also increased. b USP48 cannot cleave BRCA1-initiated H2A monoubiquitination efficiently, therefore SMARCAD1 can bind and initiate downstream signaling. c A second ubiquitination on H2A can activate USP48, cleaving BRCA-initiated ubiquitination; therefore, SMARCAD1 cannot engage with the nucleosome anymore and signaling is stopped