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BRCA1 deficiencies cause breast, ovarian, prostate and other cancers, and render tumours hypersensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. To understand the resistance mechanisms, we conducted whole-genome CRISPR–Cas9 synthetic-viability/resistance screens in BRCA1-deficient breast cancer cells treated with PARP inhibitors. We identified two previously uncharacterized proteins, C20orf196 and FAM35A, whose inactivation confers strong PARP-inhibitor resistance. Mechanistically, we show that C20orf196 and FAM35A form a complex, ‘Shieldin’ (SHLD1/2), with FAM35A interacting with single-stranded DNA through its C-terminal oligonucleotide/oligosaccharide-binding fold region. We establish that Shieldin acts as the downstream effector of 53BP1/RIF1/MAD2L2 to promote DNA double-strand break (DSB) end-joining by restricting DSB resection and to counteract homologous recombination by antagonizing BRCA2/RAD51 loading in BRCA1-deficient cells. Notably, Shieldin inactivation further sensitizes BRCA1-deficient cells to cisplatin, suggesting how defining the SHLD1/2 status of BRCA1-deficient tumours might aid patient stratification and yield new treatment opportunities. Highlighting this potential, we document reduced SHLD1/2 expression in human breast cancers displaying intrinsic or acquired PARP-inhibitor resistance. Through CRISPR–Cas9 screen, Dev et al. identified that SHLD1/2 inhibition contributes to PARP-inhibitor resistance. Mechanistically, SHLDs promote non-homologous end-joining and antagonize homologous recombination.

Radical prostatectomy remains the gold-standard treatment for clinically localized prostate cancer. Although cancer control is the primary goal, secondary outcomes such as continence recovery are of great importance to patients. Thus, it is a challenge for prostate cancer surgeons to optimize continence outcomes without compromising oncologic results. Many high-volume surgeons have demonstrated excellent long-term continence rates in their patients, but early continence is variable and less than ideal even in expert hands. A plethora of individual technical maneuvers exist to optimize early recovery of continence, but as yet there is no composite technique that incorporates the relevant anatomic principles of minimizing damage to the urinary sphincters and their nerves, maximizing functional urethral length, creating a secure and watertight vesicourethral anastomosis, providing circumferential fascioligamentous support to the anastomosis and external sphincter, and ameliorating postoperative bladder descent. Our ten-step approach to collating these individual maneuvers into a unified technique could be used by surgeons to obtain the best possible early recovery of urinary control for their patients, without risking their oncologic outcomes.