Mfd – at the crossroads of bacterial DNA repair, transcriptional regulation and molecular evolvability

The development of bacteriophage T7 was examined in an Escherichia coli double mutant defective for the two major apurinic, apyrimidinic endonucleases (exonuclease III and endonuclease IV, xth nfo). In cells infected with phages containing apurinic sites, the defect in repair enzymes led to a decrease of phage survival and a total absence of bacterial DNA degradation and of phage DNA synthesis. These results directly demonstrate the toxic action of apurinic sites on bacteriophage T7 at the intracellular level and its alleviation by DNA repair. In addition, untreated T7 phage unexpectedly displayed reduced plating efficiency and decreased DNA synthesis in the xth nfo double mutant.Key words: apurinic sites, DNA repair, T7 phage.

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The Nuclear Lamina: Protein Accumulation and Disease

Biomedicines ◽

10.3390/biomedicines8070188 ◽

2020 ◽

Vol 8 (7) ◽

pp. 188

Author(s):

Carla Almendáriz-Palacios ◽

Zoe E. Gillespie ◽

Matthew Janzen ◽

Valeria Martinez ◽

Joanna M. Bridger ◽

...

Keyword(s):

Dna Repair ◽

Protein Synthesis ◽

Transcriptional Regulation ◽

Nuclear Envelope ◽

Genome Organization ◽

Nuclear Lamina ◽

Protein Accumulation ◽

Protein Levels ◽

Protein Clearance ◽

Serious Disease

Cellular health is reliant on proteostasis—the maintenance of protein levels regulated through multiple pathways modulating protein synthesis, degradation and clearance. Loss of proteostasis results in serious disease and is associated with aging. One proteinaceous structure underlying the nuclear envelope—the nuclear lamina—coordinates essential processes including DNA repair, genome organization and epigenetic and transcriptional regulation. Loss of proteostasis within the nuclear lamina results in the accumulation of proteins, disrupting these essential functions, either via direct interactions of protein aggregates within the lamina or by altering systems that maintain lamina structure. Here we discuss the links between proteostasis and disease of the nuclear lamina, as well as how manipulating specific proteostatic pathways involved in protein clearance could improve cellular health and prevent/reverse disease.

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GENE-41. UNDERSTANDING THE DIFFERENCES IN ADOLESCENT AND YOUNG ADULT (AYA) GLIOMAS AND OLDER ADULT (OA) GLIOMAS BASED ON FUNCTIONAL MOLECULAR SUBGROUPS

Neuro-Oncology ◽

10.1093/neuonc/noz175.443 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi106-vi106

Author(s):

Catherine Bi ◽

Ashwin Subramaniam ◽

Joanne Xiu ◽

Amy Heimberger ◽

Sharon Michelhaugh ◽

...

Keyword(s):

Dna Repair ◽

Transcriptional Regulation ◽

Tumor Suppressor ◽

Metabolic Pathways ◽

Tumor Suppressor Genes ◽

Mutation Frequency ◽

Pik3ca Mutation ◽

Low Grade ◽

Suppressor Genes ◽

Pathway Gene

Abstract BACKGROUND Gliomas in the AYA population (15–39 years of age) have unique biological characteristics and need to be better characterized. METHODS Glioma tumors in AYA subjects and subjects >65 years of age (OA) were analyzed by next generation sequencing using a 592 gene panel. Pathogenic mutations were classified into five functional groups, viz. metabolic pathways genes (IDH1/2, FH), tumor suppressor genes (TP53, RB1, APC, NF1/2, PTEN, TSC1/2), genes involved in DNA repair (MMR genes, BRCA1/2, POLE, ARID1A, CHEK2, ATM, BLM, BRIP1, WRN, BARD1, POT1, MUTYH), oncogenes (BRAF, NRAS, HRAS, EGFR, PDGFRA, FGFR1, NOTCH1, MYCN), and genes involved in transcriptional regulation (SETD2, H3F3A, KMTD2A/2C/2D, KDM6A, PIK3CA). Mutation frequency in AYA tumors and OA tumors were compared using Chi-squared analysis (Pearson’s score χ2; likelihood ratio LR). RESULTS 720 unique gliomas tumors were analyzed: 118 AYA, 602 OA; 420 males, 300 females. When both groups are considered together, glioblastoma was the most common histology (75%), followed by grade 3 astrocytoma (13%), glioma NOS (3.8%), oligodendrogliomas (3%), low grade gliomas (2.9%) and other (2.3%). AYA tumors harbored more metabolic pathway gene mutations (χ2 137.7, p< 0.0001) driven primarily by IDH1 mutations, while OA tumors had a higher mutation frequency in oncogenes (χ2 9.22, p=0.0024) driven by EGFR mutations (LR 27.567) and tumor suppressor genes (χ2 40.35, p< 0.0001) driven by NF1 (LR 18.147) and PTEN (LR 66.216). No significant differences were noted in mutation frequency in DNA repair or transcriptional regulation genes. However, AYA glioblastoma tumors had a significant increase in mutations in genes involved in chromatin remodeling, (χ2 11.43, p=0.0007) even after excluding H3F3A. CONCLUSIONS Functional genomic classification of AYA tumors may help develop better targeted therapies, especially focused on genes involved in metabolic pathways and transcriptional regulation.

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