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Irradiation-induced damage and the DNA damage response
Published in Michael C. Joiner, Albert J. van der Kogel, Basic Clinical Radiobiology, 2018
Conchita Vens, Marianne Koritzinsky, Bradly G. Wouters
To enable homology search, invasion and annealing, helicases such as BLM help unwind DNA from its tightly organized structure. When an undamaged DNA template is identified and presented, DNA polymerases can synthesize across the missing regions of the damaged site, thereby accurately repairing the break. The crossover structure that results from this has to be reversed to reset the chromatin to its original configuration. This is done with specialized nucleases which cut or resolve the junctions, followed finally by ligation of adjacent ends. Structure-specific endonucleases such as the human MUS81 complex and SLX4 and SLX1 are also involved in untangling the DNA and assist the resolution of these complicated structures that are formed during strand invasion and template replication. The RMI complex (BLM, BLAP75, TOP3α) is important to limit DNA crossover. Cells become more radiation resistant in late S and G2 phases of the cell cycle as HR becomes available as a DSBR pathway (30).
Genetic and epigenetic regulation of natural resistance to HIV-1 infection: new approaches to unveil the HESN secret
Published in Expert Review of Clinical Immunology, 2020
Claudio Fenizia, Irma Saulle, Mario Clerici, Mara Biasin
GWAS (genome-wide association studies), which investigate common gene variant’s role in HIV infection, explain approximately 20% of viral load variation and disease progression, suggesting that other still unknown factors are involved in the control of this disease. Notably, innovative technologies in genome sequencing allow the identification of uncommon variants as well, both by sequencing of the entire exome (2% of the genome), or through the deep sequencing of the complete genome or transcriptome (RNA-seq). In 2018, a study published by Nissen et al. on whole exome sequencing (WES) on 7 LTNPs and 4 ECs led to the identification of 24 relevant variants localized in 20 different genes, mainly encoding innate immune sensors (LRRIF1P, IRAK2, TAB2, NOD2, SLX4) and proteins involved in HIV uptake and intracellular trafficking (FN1, FRK, PIK3C2B, PIK3R5, MAP1A, PIK3R6) [185]. However, no single unifying mechanism common to both ECs and LTNPs was identified, suggesting that slow disease progression in these two different phenotypes may depend on a diverse genetic background.
Roles of homologous recombination in response to ionizing radiation-induced DNA damage
Published in International Journal of Radiation Biology, 2023
Jac A. Nickoloff, Neelam Sharma, Christopher P. Allen, Lynn Taylor, Sage J. Allen, Aruna S. Jaiswal, Robert Hromas
Three nucleases have been implicated in cleavage of blocked or stalled replication forks, yielding replication-dependent DSBs. MUS81 is an ancient, 3′ structure-specific endonuclease that is assisted by EME1 or EME2 co-factors. MUS81/EME2 cleaves blocked or stalled replication forks to promote accurate fork restart Defects in MUS81 or EME2 inhibit restart of stressed replication forks, and increase genome instability (Pepe and West 2014a). As noted above, HJs in HR intermediates can be resolved by MUS81/EME1 or SLX4/GEN1. Of note, SLX4 also assists MUS81 in cleaving stressed replication forks, and it also regulates GEN1 activity during fork processing (Malacaria et al. 2017). EEPD1 is a 5′ structure-specific endonuclease that arose ∼500 million years ago in chordates and early vertebrates. Metnase is another 5′ structure-specific endonuclease that evolved much later, first appearing in monkeys ∼50 million years ago (Cordaux et al. 2006). Defects in either EEPD1 or Metnase slow restart of stressed replication forks and increase the frequency of forks that fail to restart within 20-30 min of release from replication stress (De Haro et al. 2010; Wu et al. 2015; Kim et al. 2017; Sharma et al. 2020). Metnase also promotes NHEJ and TopoIIα-dependent chromosome decatenation (Lee et al. 2005; Hromas et al. 2008; Wray et al. 2009a, 2009b; Fnu et al. 2011). Despite the similarities between EEPD1 and Metnase, recent evidence indicates that only EEPD1 cleaves stalled/blocked forks. Metnase has both protein methylation and nuclease activities, both of which are important for timely, HR-mediated restart of stalled replication forks (Kim et al. 2014; Kim et al. 2015). This suggests that Metnase nuclease may function later during fork restart, perhaps trimming flaps that arise during fork processing (Sharma et al. 2020). Once EEPD1 cleaves stalled forks, it recruits EXO1 to initiate resection of the resulting single-ended DSBs, thereby suppressing (genome-destabilizing) NHEJ and promoting (genome-stabilizing) HR-mediated fork repair and restart (Wu et al. 2015; Kim et al. 2017). Interestingly, Metnase also promotes EXO1 resection at stressed replication forks (Kim et al. 2017).