RESUMO
The BRCA1/BARD1 complex plays a key role in the repair of DNA double-strand breaks (DSBs) in both somatic cells and germ cells. However, the underlying molecular mechanism by which this complex mediates DSB repair is not fully understood. Here, we examined the XY body of male germ cells, where DSBs are accumulated. We show that the recruitment of the BRCA1/BARD1 complex to the unsynapsed axis of the XY body is mediated by pre-ribosomal RNA (pre-rRNA). Similarly, the BRCA1/BARD1 complex associates with pre-rRNA in somatic cells, which not only forms nuclear foci in response to DSBs, but also targets the BRCA1/BARD1 complex to DSBs. The interactions between the BRCT domains of the BRCA1/BARD1 complex and pre-rRNA induce liquid-liquid phase separations, which may be the molecular basis of DSB-induced nuclear foci formation of the BRCA1/BARD1 complex. Moreover, cancer-associated mutations in the BRCT domains of BRCA1 and BARD1 abolish their interactions with pre-rRNA. Pre-rRNA also mediates BRCA1-dependent homologous recombination, and suppression of pre-rRNA biogenesis sensitizes cells to PARP inhibitor treatment. Collectively, this study reveals that pre-rRNA is a functional partner of the BRCA1/BARD1 complex in the DSB repair.
RESUMO
OBJECTIVES: To determine disparities in rates, length of stay (LOS) and hospital costs of potentially preventable hospitalisations (PPH) for selected chronic conditions among Aboriginal and non-Aboriginal South Australians (SA), then examine associations with area-level socioeconomic disadvantage and remoteness. SETTING: Period prevalence study using linked, administrative public hospital records. PARTICIPANTS: Participants included all SA residents in 2005-2006 to 2010-2011. Analysis focused on those individuals experiencing chronic PPH as defined by the Australian Institute of Health and Welfare. PRIMARY OUTCOME MEASURES: Number and rates (unadjusted, then adjusted for sex and age) of chronic PPH, total LOS and direct hospital costs by Aboriginality. RESULTS: Aboriginal SAs experienced higher risk of index chronic PPH compared with non-Aboriginals (11.5 and 6.2 per 1000 persons per year, respectively) and at younger ages (median age 48 vs 70 years). Once hospitalised, Aboriginal people experienced more chronic PPH events, longer total LOS with higher costs than non-Aboriginal people (2.6 vs 1.9 PPH per person; 11.7 vs 9.0 days LOS; at $A17 928 vs $A11 515, respectively). Compared with population average LOS, the standardised rate ratio of LOS among Aboriginal people increased by 0.03 (95% CI 0.00 to 0.07) as disadvantage rank increased and 1.04 (95% CI 0.63 to 1.44) as remoteness increased. Non-Aboriginal LOS also increased as disadvantage increased but at a lower rate (0.01 (95% CI 0.01 to 0.01)). Costs of Aboriginal chronic PPH increased by 0.02 (95% CI 0.00 to 0.06) for each increase in disadvantage and 1.18 (95% CI 0.80 to 1.55) for increased remoteness. Non-Aboriginal costs also increased as disadvantage increased but at lower rates (0.01 (95% CI 0.01 to 0.01)). CONCLUSION: Aboriginal people's heightened risk of chronic PPH resulted in more time in hospital and greater cost. Systematic disparities in chronic PPH by Aboriginality, area disadvantage and remoteness highlight the need for improved uptake of effective primary care. Routine, regional reporting will help monitor progress in meeting these population needs.
