Summary Although the BBAP E3 ligase and its binding partner, BAL, are overexpressed in chemotherapy-resistant lymphomas, the role of these proteins in DNA damage responses remains undefined. Since BAL proteins modulate promoter-coupled transcription and contain structural motifs associated with chromatin remodeling and DNA repair, we reasoned that the BBAP E3 ligase might target nucleosomal proteins. Herein, we demonstrate that BBAP selectively monoubiquitylates histone H4 lysine 91 and protects cells exposed to DNA damaging agents. Disruption of BBAP-mediated monoubiquitylation of histone H4K91 is associated with the loss of chromatin-associated H4K20 methylase, mono- and dimethyl H4K20, and a delay in the kinetics of 53BP1 foci formation at sites of DNA damage. Since 53BP1 localizes to DNA damage sites, in part, via an interaction with dimethyl H4K20, these data directly implicate BBAP in the monoubiquitylation and additional post-translational modification of histone H4 and an associated DNA damage response.
The BAL1 macrodomain-containing protein and its partner E3 ligase, BBAP, are overexpressed in chemotherapy-resistant lymphomas. BBAP selectively ubiquitylates histone H4 and indirectly promotes early 53BP1 recruitment to DNA damage sites. However, neither BBAP nor BAL1 has been directly associated with a DNA damage response (DDR), and the function of BAL1 remains undefined. Herein, we describe a direct link between rapid and short-lived poly(ADP-ribose) (PAR) polymerase 1 (PARP1) activation and PARylation at DNA damage sites, PAR-dependent recruitment of the BAL1 macrodomain-containing protein and its partner E3 ligase, local BBAP-mediated ubiquitylation, and subsequent recruitment of the checkpoint mediators 53BP1 and BRCA1. The PARP1-dependent localization of BAL1-BBAP functionally limits both early and delayed DNA damage and enhances cellular viability independent of ATM, MDC1, and RNF8. These data establish that BAL1 and BBAP are bona fide members of a DNA damage response pathway and are directly associated with PARP1 activation, BRCA1 recruitment, and double-strand break repair.
The BAL1 macro domain-containing protein and its partner E3 ligase, BBAP, are overexpressed in chemotherapy-resistant lymphomas. BBAP selectively ubiquitylates histone H4 and indirectly promotes early 53BP1 recruitment to DNA damage sites. However, neither BBAP nor BAL1 have been directly associated with a DNA damage response (DDR) and the function of BAL1 remains undefined. DDR proteins assemble in a coordinated, sequential manner at sites of DNA breaks. The initial recruitment phase is rapid, transient and dependent upon PARylation at DNA damage sites. A second phase, which also begins within seconds but lasts for hours, includes the sequential phosphorylation of ATM, MDC1 and the RNF8-dependent ubiquitylation of multiple double-strand break (DSB) repair factors. We have now defined a direct link between the rapid and short-lived PARP1 activation and PARylation at DNA damage sites, PAR-dependent recruitment of the BAL1 macro domain-containing protein and its partner BBAP E3 ligase, local BBAP-mediated ubiquitylation and subsequent recruitment of the checkpoint mediators, 53BP1 and BRCA1. The PARP1-dependent localization of BAL1/BBAP functionally limits both early and delayed DNA damage and enhances cellular viability independent of ATM, MDC1 and RNF8. These data establish BAL1 and BBAP as bona fide DDR pathway members and directly associate PARP1 activation, BRCA1 recruitment and DSB repair. Citation Format: Qingsheng Yan, Rong Xu, Liya Zhu, Xin Cheng, Zhe Wang, John Manis, Margaraet Shipp. BAL1 and its partner E3 Ligase, BBAP, Link PARP activation, Ubiquitylation and double-strand DNA repair independent of ATM, MDC1 and RNF8. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 633. doi:10.1158/1538-7445.AM2013-633
Somatic cell nuclear transfer (SCNT), cell fusion, and induced pluripotent stem cells (iPSCs) technologies are three strategies that allow reprogramming somatic cells into the pluripotent state; however, the efficiency is low and the mechanisms are not fully clear. In addition, there are reports that changes in chromatin play a critical role in these reprogramming strategies by modulating binding of transcription factors to their targets. In this review, we mainly discuss inactivation of the X chromosome, chromatin decondensation and remodeling, histone modifications, and histone variants in the three strategies. This review will provide an insight for future nuclear reprogramming research.
3958 Poster Board III-894 Although the BBAP E3 ligase and its binding partner, BAL, are overexpressed in chemotherapy-resistant diffuse large B-cell lymphomas (DLBCLs), the role of these proteins in response to DNA damage remains undefined. The BBAP and BAL1 genes are located on chromosome 3q21 in a head-to-head orientation and regulated by the same gIFN-responsive bidirectional promoter. These findings are of note because BBAP and BAL1 are most abundant in DLBCLs with a prominent, but ineffective, immune/inflammatory infiltrate and increased gIFN production. Since BAL proteins modulate promoter-coupled transcription and contain structural motifs associated with chromatin remodeling and DNA repair, we reasoned that the BBAP E3 ligase might target nucleosomal proteins. The nucleosome consists of eight core histone proteins (two each of H2A, H2B, H3 and H4) encircled by a genomic DNA segment. Individual histone proteins undergo extensive post-translational modifications that are essential for proper chromatin assembly, regulation of chromatin structure and DNA damage repair. We found that the BBAP E3 ligase selectively monoubiquitylated histone H4 lysine 91, interacted with the chromatin-associated histone and protected cells exposed to DNA damaging agents. For these reasons, we visually assessed the role of BBAP in the DNA damage response (DDR) pathway. DNA damage generates double-strand DNA breaks and the relocalization of DDR factors to damaged chromatin with phosphorylated ATM, g-H2AX, and MDC-1 accumulating early in the response, followed by 53BP-1 and BRCA1. BBAP-depletion did not affect the accumulation of the early response factors, ATM, g-H2AX or MDC, to sites of DNA damage. In marked contrast, BBAP-depletion significantly altered the DDR response to the checkpoint mediator, 53BP1. At 1 - 4 hrs following induction of DNA damage, there were significantly fewer 53BP1 foci in BBAP-depleted cells than in controls. Since 53BP1 is recruited to histones via the specific interaction of its tandem tudor domains with mono- and dimethyl H4K20, we next compared BBAP expression, H4 monoubiquitylation and H4K20 methylation in control and BBAP-depleted cells at serial timepoints following DNA damage. In parental or control siRNA-treated Hela cells, DNA damage increased the abundance of BBAP and the respective histone H4 modifications - monoubiquitylated histone H4 and mono- and dimethylated H4K20 – with similar kinetics. However, when BBAP was depleted prior to DNA damage, there was a significant decrease in monoubiquitylated histone H4 and mono- and dimethylated histone H4K20. Taken together, these data directly associate BBAP-mediated monoubiquitylation of histone H4 with the additional histone H4 modifications, H4K20 mono- and dimethylation, necessary for 53BP1 recruitment. PR-Set7/Set8 catalyses the monomethylation of histone H4K20, which is a prerequisite for H4K20 dimethylation. Since histone H4K20 mono- and dimethylation were significantly reduced in BBAP-depleted cells, we next assessed PR-Set7/Set8 levels following BBAP knockdown. BBAP depletion significantly decreased the abundance of chromatin-associated PR-Set7/Set8, providing a likely mechanism for BBAP-associated changes in histone H4K20 methylation and 53BP1 foci formation. BBAP-mediated monoubiquitylation of H4K91 and modulation of an associated DNA damage response may represent a mechanism of gIFN-mediated “immunoediting”, limiting the host reponse against lymphoma. More generally, BBAP's role in decreasing the efficacy of chemotherapy-induced DNA damage responses has implications for the design of more effective treatment regimens. Disclosures: No relevant conflicts of interest to declare.
Mean corpuscular hemoglobin (MCH) is a common blood routine test index. To explore the relationship between MCH and length of hospital stay in patients with acute pancreatitis (AP), we included 273 patients with AP without coronary heart disease, diabetes, hypertension and anemia in this study. All data were separated into three groups according to the length of hospital stay. Gender (p = 0.017) and severity classification (p < 0.001) were significantly correlated with length of hospital stay among three groups. Notably, MCH level was significant different among three groups (p = 0.009). Thus, all data were separated into two groups according to MCH level, and significant increases in the length of hospital stay were observed between two groups (p = 0.030). A positive correlation between length of hospital stay and MCH was observed (r = 0.172, p = 0.004). Multiple linear regression analysis showed that MCH was independent correlated with the length of hospital stay, no matter whether severity classification of AP was included (beta = 0.248, p < 0.001; beta = 0.212, p < 0.001). Our results demonstrated that the length of hospital stay was correlated with MCH level in patients with AP, and MCH level at admission may predict the length of hospital stay independent of severity classification in AP. These results may provide a potential evaluation basis for the management of patients with AP.
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