Protein kinases are central to regulation of cellular signaling in the eukaryotes. Wellconserved and lineage-specific protein kinases have previously been identified from various completely sequenced genomes of eukaryotes. The current work describes a genome-wide analysis for protein kinases encoded in the Plasmodium falciparum genome. Using a few different profile matching methods, we have identified 99 protein kinases or related proteins in the parasite genome. We have classified these kinases into subfamilies and analyzed them in the context of noncatalytic domains that occur in these catalytic kinase domain-containing proteins.

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Recognition and repair of double-stranded DNA breaks (DSB) involves the targeted recruitment of BRCA tumor suppressors to damage foci through binding of both ubiquitin (Ub) and the Ub-like modifier SUMO. RAP80 is a component of the BRCA1 A complex, and plays a key role in the recruitment process through the binding of Lys 63 -linked poly-Ub chains by tandem Ub interacting motifs (UIM). RAP80 also contains a SUMO interacting motif (SIM) just upstream of the tandem UIMs that has been shown to specifically bind the SUMO-2 isoform. The RAP80 tandem UIMs and SIM function collectively for optimal recruitment of BRCA1 to DSBs, although the molecular basis of this process is not well understood. Using NMR spectroscopy, we demonstrate that the RAP80 SIM binds SUMO-2, and that both specificity and affinity are enhanced through phosphorylation of the canonical CK2 site within the SIM. The affinity increase results from an enhancement of electrostatic interactions between the phosphoserines of RAP80 and the SIM recognition module within SUMO-2. The NMR structure of the SUMO-2⅐phospho-RAP80 complex reveals that the molecular basis for SUMO-2 specificity is due to isoform-specific sequence differences in electrostatic SIM recognition modules.The DNA repair process in eukaryotic cells is an indispensible life process responsible for maintaining the fidelity of the genome (1, 2). The genomic information encoded within the molecular structure of DNA is relentlessly compromised as a result of factors that include free radicals arising from metabolic processes, radiation, and replication errors (1). By virtue of highly regulated and efficient DNA repair mechanisms, most DNA damage does not progress to viable malignant tumors (1). Among the different kinds of damage that alter DNA structure, double strand breaks are the most deleterious (1). Depending on the nature of DNA damage, checkpoint activation and cell cycle arrest accompany a number of repair pathways, including homologous recombination, non-homologous end joining, or alternative non-homologous end joining repair, which function to combat the damage (3). Similar to many life processes, homologous recombination is governed by the hierarchical and synergistic action of various post-translational modifications, such as phosphorylation, ubiquitination, and SUMOylation (4, 5). The severed ends of damaged DNA are sensed by the MRE11/Rad50/NBS1 (MRN) protein complex, followed by recruitment of ATM kinase and its concomitant activation (3,5,6). This results in the phosphorylation of nearby histones, which serves as a marker for initiation of repair (3, 5). Phosphorylated histones comprise the binding site for MDC1, which is also phosphorylated by ATM kinase; subsequently, phosphorylated MDC1 recruits the ubiquitination enzyme RNF8, which acts with the Ubc13/Mms2 heterodimer to attach Lys 63 -linked Ub chains at damaged sites, in combination with the Ub 2 ligase RNF168 (3,7,8). One of the biological functions for Lys 63 -linked poly-Ub chains is to serve as a signal for BRCA1 recru...

The neurotoxic level of ammonia in the brain during liver cirrhosis causes a nervous system disorder, hepatic encephalopathy (HE), by affecting mitochondrial functions. Sirtuin‐3 (SIRT3) is emerging as a master regulator of mitochondrial integrity, which is currently being focused as a pathogenic hotspot for HE. This article describes SIRT3 level versus mitochondrial dysfunction markers in the hippocampus of the control, the moderate‐grade hepatic encephalopathy (MoHE), developed in thioacetamide‐induced (100 mg/kg bw ip for 10 days) liver cirrhotic rats, and the MoHE rats treated with an SIRT3 activator, honokiol (HKL; 10 mg/kg bw ip), for 7 days from 8th day of the thioacetamide schedule. As compared with the control group rats, hippocampus mitochondria of MoHE rats showed a significant decline in SIRT3 expression and its activity with concordant enhancement of ROS and declined membrane permeability transition and organelle viability scores. This was consistent with the declined mitochondrial thiol level and thiol‐regenerating enzyme, isocitrate dehydrogenase 2. Also, significantly declined activities of electron transport chain complexes I, III, IV, and Q10, decreased NAD+/NADH and ATP/AMP ratios, and enhanced number of the shrunken mitochondria were recorded in the hippocampus of those MoHE rats. However, all these mitochondrial aberrations were observed to regain their normal profiles/levels, concordant to the enhanced SIRT3 expression and its activity due to treatment with HKL. The findings suggest a role of SIRT3 in mitochondrial structure–function derangements associated with MoHE pathogenesis and SIRT3 activation by HKL as a relevant strategy to protect mitochondrial integrity during ammonia neurotoxicity.

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