Breast cancer gene 1 ( BRCA1 ) deficient cells not only are hypersensitive to double-strand breaks but also are hypersensitive to UV irradiation and other agents that cause replication blockade; however, the molecular mechanisms behind these latter sensitivities are largely unknown. Here, we report that BRCA1 promotes cell survival by directly regulating the DNA damage tolerance pathway in response to agents that create cross-links in DNA. We show that BRCA1 not only promotes efficient mono- and polyubiquitination of proliferating cell nuclear antigen (PCNA) by regulating the recruitment of replication protein A, Rad18, and helicase-like transcription factor to chromatin but also directly recruits translesion polymerases, such as Polymerase eta and Rev1, to the lesions through protein–protein interactions. Our data suggest that BRCA1 plays a critical role in promoting translesion DNA synthesis as well as DNA template switching.

SummaryDNA damage response (DDR) and the centrosome cycle are two of the most critical processes for maintaining a stable genome in animals. Sporadic evidence suggests a connection between these two processes. Here, we report our findings that six Fanconi Anemia (FA) proteins, including FancI and FancJ, localize to the centrosome. Intriguingly, we found that the localization of FancJ to the mother centrosome is stimulated by a DNA interstrand crosslinker, Mitomycin C (MMC). We further show that, in addition to its role in interstrand crosslinking (ICL) repair, FancJ also regulates the normal centrosome cycle as well as ICL induced centrosome amplification by activating the polo-like kinase 1 (PLK1). We have uncovered a novel function of FancJ in centrosome biogenesis and established centrosome amplification as an integral part of the ICL response.

BACKGROUND AND PURPOSE:Previous studies have shown perfusion abnormalities in the thalamus and upper brain stem in patients with epilepsy with impaired consciousness. We hypothesized that these areas associated with consciousness will also show metabolic abnormalities. However, metabolic abnormalities in those areas correlated with consciousness has not been characterized with multiplevoxel 1 H-MRS. In this study, we investigated the metabolic alterations in these brain regions and assessed the correlation between seizure features and metabolic alterations. MATERIALS AND METHODS:Fifty-seven patients with epilepsy and 24 control subjects underwent routine MR imaging and 3D multiplevoxel 1 H-MRS. Patients were divided into 3 subgroups: focal impaired awareness seizures (n ϭ 18), primary generalized tonic-clonic seizures (n ϭ 19), and secondary generalized tonic-clonic seizures (n ϭ 20). The measured metabolite alterations in NAA/Cr, NAA/(Cr ϩ Cho), and Cho/Cr ratios in brain regions associated with the consciousness network were compared between the patient and control groups. ROIs were placed in the bilateral inferior frontal gyrus, supramarginal gyrus, cingulate gyrus, precuneus, thalamus, and upper brain stem. Correlations between clinical parameters (epilepsy duration and seizure frequency) and metabolite alterations were analyzed. RESULTS:Significantly lower NAA/Cr and NAA/(Cho ϩ Cr) ratios (P Ͻ .05 and Ͻ .01, respectively) were observed in the bilateral thalamus and upper brain stem in all experimental groups, and significantly high Cho/Cr ratios (P Ͻ .05) were observed in the right thalamus in the focal impaired awareness seizures group. There were no significant differences in metabolite ratios among the 3 patient groups (P Ͼ .05). The secondary generalized tonic-clonic seizures group showed a negative correlation between the duration of epilepsy and the NAA/ (Cr ϩ Cho) ratio in the bilateral thalamus (P Ͻ .05). CONCLUSIONS:Metabolic alterations were observed in the brain stem and thalamus in patients with epilepsy with impaired consciousness.ABBREVIATIONS: FIAS ϭ focal impaired awareness seizures; PGTCS ϭ primary generalized tonic-clonic seizures; SGTCS ϭ secondary generalized tonic-clonic seizures E pilepsy is a devastating illness of the nervous system. Studies

a 41. Pathania S, et al. (2011) BRCA1 is required for postreplication repair after UV-induced DNA damage. Mol Cell 44(2):235-251.

Neuroimaging evidence implies that cognitive impairment in patients with end-stage renal disease (ESRD) is related to the disruption of the default-mode network (DMN). The DMN can be divided into three functionally independent subsystems, which include the cortical hub subsystem [consisting of the posterior cingulate cortex (PCC) and the anterior medial prefrontal cortex (aMPFC)], the dorsal medial prefrontal cortex (dMPFC) subsystem, and the medial temporal lobe (MTL) subsystem. However, it is unknown how the functional connectivity (FC) in DMN subsystems is differentially impaired in ESRD. This prospective study was carried out at the Affiliated Hospital of Qingdao University, China, between August 2018 and July 2020. Thirty-two ESRD patients and forty-five healthy controls (HCs) were recruited for this study and received resting-state functional magnetic resonance imaging (rs-fMRI) scanning, and FCs on predefined regions of interest (ROIs) were individually calculated in three DMN subsystems using both ROI-and seed-based FC analyses to examine FC alterations within and between DMN subsystems. The two-sample t-test was used for the comparisons between groups. We also tested the associations between FC changes and clinical information using Pearson's correlation analysis. The results demonstrated that ESRD patients, compared with HCs, exhibit reduced FC specifically within the cortical hubs and between the DMN hubs and two subsystems (the dMPFC and MTL subsystems). Moreover, the FC values between the aMPFC and PCC were positively correlated with creatinine and urea levels in the ESRD patients. Our results suggest that the cortical hubs (PCC and aMPFC) are preferentially disrupted and that other subsystems may be progressively damaged to a certain degree as the disease develops.