Background: 53BP1 counteracts BRCA1 in DNA repair. Results: RIF1 acts downstream of 53BP1 and counteracts BRCA1 in DNA end resection. It also has a 53BP1-independent role in regulating BLM chromatin association. Conclusion: RIF1 is the major downstream effector of 53BP1. Significance: These results reveal that RIF1 antagonizes BRCA1, functions in DNA end protection, and prevents homologous recombination repair.

Through an shRNA-mediated loss-of-function screen, we identified PTPN14 as a potential tumor suppressor. PTPN14 interacts with yes-associated protein 1 (YAP1), a member of the hippo signaling pathway. We showed that PTPN14 promotes the nucleus-to-cytoplasm translocation of YAP1 during contact inhibition and thus inhibits YAP1 transactivation activity. Interestingly, PTPN14 protein stability was positively controlled by cell density. We identified the CRL2 LRR1 (cullin2 RING ubiquitin ligase complex/leucine-rich repeat protein 1) complex as the E3 ligase that targets PTPN14 for degradation at low cell density. Collectively, these data suggest that PTPN14 acts to suppress cell proliferation by promoting cell density-dependent cytoplasmic translocation of YAP1.

Ubiquitination cascade plays an important role in the assembly of repair and signaling proteins at sites of double-strand DNA breaks (DSBs). E3 ubiquitin ligase RNF8 triggers initial ubiquitination at DSBs, whereas substained ubiquitination requires downstream E3 ligase RNF168. It is not yet known whether RNF8 and RNF168 have discrete substrates and/or form different ubiquitin chains. Here we show that RNF168 acts with E2 enzyme UBC13 and specifically synthesizes lysine 63 (K63)-linked chains, whereas RNF8 forms mainly K48-linked chains on chromatin, promoting substrate degradation. We also find that RNF8 regulates the abundance of NHEJ repair protein KU80 at sites of DNA damage, and RNF8 depletion resulted in prolonged retention of KU80 at damage sites and impaired non-homologous end joining (NHEJ) repair. These findings reveal a distinct feature of RNF8 and indicate the involvement of ubiquitination-mediated degradation pathway in DNA damage repair.

Epstein-Barr virus (EBV) infection is ubiquitous worldwide and is associated with multiple cancers, including nasopharyngeal carcinoma (NPC). The importance of EBV viral genomic variation in NPC development and its striking epidemic in southern China has been poorly explored. Through large-scale genome sequencing of 270 EBV isolates and two-stage association study of EBV isolates from China, we identified two non-synonymous EBV variants within BALF2 strongly associated with the risk of NPC (odds ratio (OR) = 8.69, P=9.69×10−25 for SNP 162476_C; OR = 6.14, P=2.40×10−32 for SNP 163364_T). The cumulative effects of these variants contributed to 83% of the overall risk of NPC in southern China. Phylogenetic analysis of the risk variants revealed a unique origin in Asia, followed by clonal expansion in NPC-endemic regions. Our results provide novel insights into NPC endemic in southern China and also enable the identification of high-risk individuals for NPC prevention.

The product of breast cancer susceptibility gene 1, BRCA1, plays pivotal roles in the maintenance of genomic integrity. Mounting evidence indicates that BRCA1 associates with many proteins or protein complexes to regulate diverse processes important for the cellular response to DNA damage. One of these complexes, which mediates the accumulation of BRCA1 at sites of DNA breaks, involves the ubiquitin-binding motif (UIM)-containing protein RAP80, a coiled-coil domain protein CCDC98/Abraxas, and a deubiquitinating enzyme BRCC36. Here we describe the characterization of a novel component of this complex, MERIT40 (Mediator of Rap80 Interactions and Targeting 40 kd), which together with an adaptor protein BRE/BRCC45, enforces the BRCA1-dependent DNA damage response. MERIT40 is assembled into this RAP80/CCDC98-containing complex via its direct interaction with BRE/BRCC45. Importantly, MERIT40 regulates BRCA1 retention at DNA breaks and checkpoint function primarily via a role in maintaining the stability of BRE and this five-subunit protein complex at sites of DNA damage. Together, our study reveals that a stable complex containing MERIT40 acts early in DNA damage response and regulates damage-dependent BRCA1 localization.[Keywords: MERIT40; RAP80; CCDC98/Abraxas; BRE/BRCC45; BRCC36; BRCA1] Supplemental material is available at http://www.genesdev.org.