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DNA Double Strand Breaks and Chromosomal Aberrations
Published in K. H. Chadwick, Understanding Radiation Biology, 2019
However, it is worth noting that although the correct resolution of the Holliday junction will normally lead to perfectly repaired chromosomes, it is possible that it can also lead to a small alteration in the genetic coding of one of the chromosomes, as shown in Figure 4.18.
The Premature Aging Characteristics of RecQ Helicases
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Christ Ordookhanian, Taylor N. Dennis, J. Jefferson P. Perry
The DNA-binding activities of RecQ4 have been further characterized in recent studies, revealing that the N-terminus of human RecQ4 contains regions of intrinsic disorder, but this disorder is sufficient for strand annealing activity [148]. Multiple DNA-binding sites are observed to be present, and this N-terminal region has the highest affinity of G4 quadruplex DNA, estimated at 60-fold over other substrates that include single-stranded, double-stranded, and Y-structured DNA [148]. G4 quadruplex elements are present near origins of replication, likely highlighting RecQ4 functions in this process. A separate study also indicated the presence of two key sites in the N-terminus for DNA binding, and the helicase core contained a third that has affinity for branched substrates and in particular, Holliday junctions [149].
Genetics of mammalian meiosis
Published in C. Yan Cheng, Spermatogenesis, 2018
Formation of DSBs entails a DNA damage response, leading to phosphorylation of histone H2AX by ATM.65,66 Following generation of DSBs, SPO11 is covalently attached to the 5’ strands of both ends of the DSB. DSB breaks undergo end resection to produce 3’ single-stranded DNA (ssDNA) ends, releasing SPO11-oligonucleotide complexes.67 RPA, an ssDNA-binding complex, coats the ssDNA to protect it from degradation and prevent secondary structure formation.68 RAD51 and DMC1 are also ssDNA-binding proteins and exhibit recombinase activities. RAD51/DMC1 recombinase is loaded onto ssDNA, displaces RPA, and directs strand invasion into the duplex of the homologous chromosomes, resulting in the formation of displacement loop (D-loop).69 DMC1 is a meiosis-specific paralogue of RAD51.70 DMC1 favors repair of meiotic DSBs through a nonsister chromatid rather than a sister chromatid. The MND1/HOP2 heterodimer interacts with RAD51/DMC1 and stimulates their recombinase activity to generate the D-loop recombination intermediates.71 MCMDC2, a member of the minichromosome maintenance (MCM) helicase family, is required for RAD51- and DMC1-directed strand invasion or stabilization of recombination intermediates.72,73 MEIOB is a meiosis-specific ssDNA-binding protein.74,75 MEIOB interacts and forms a heterodimer with SPATA22, which is also a meiosis-specific protein.74,76 The MEIOB/SPATA22 complex interacts with the RPA complex and localizes to DSB sites.77 The MEIOB/SPATA22 complex has been hypothesized to function in the second end capture and maintenance of RAD51 foci.74,78 Second end capture results in the formation of the recombination intermediate–double Holliday junction (dHJ). Most proteins involved in meiotic DSB repair form foci at the DSB sites on meiotic chromosomes. Since meiotic recombination occurs in both male and female germ cells, loss of any of these recombination-related proteins leads to meiotic arrest and thus sterility in both sexes.
Targeting the DNA damage response in pediatric malignancies
Published in Expert Review of Anticancer Therapy, 2022
Jenna M Gedminas, Theodore W Laetsch
Double stranded DNA breaks can be repaired using nonhomologous end joining repair (NHEJ) or homologous recombination (HR). The repair mechanism used is based on the stability of the end of the DNA breaks [11]. NHEJ directly ligates broken DNA without the need for a homologous template [12]. Because it does not rely on a template, it is able to repair double stranded breaks in any phase of the cell cycle, however, it is also more prone to error than homologous recombination. Homologous recombination is responsible for the reactivation of stalled replication forks and repair of double stranded DNA breaks and inter-strand crosslinks [13]. The repair process occurs in three steps. The broken end of the chromosome if first paired with the homologous region on the sister chromatid. That strand is then invaded to form a Holliday junction, or DNA crossover, which generates a DNA duplex from the two different chromatids [14]. The Holliday junction is then translocated along the DNA and eventually cleaved by endonucleases to again form separate DNA molecules [14]. These two processes are activated by several kinase pathways, ataxia telangiectasia mutated (ATM), ataxia telangiectasia related (ATR), and DNA-PK, which when mutated, result in defective double-strand break repair [15].
In vitro and in vivo efficacy of Caenorhabditis elegans recombinant antimicrobial protein against Gram-negative bacteria
Published in Biofouling, 2019
Dilawar Ahmad Mir, Krishnaswamy Balamurugan
The proteomic data analysis revealed that the ABF-1 protein affected cell cycle associated proteins (Tables 2 and 3) (RuvB helicase, RecA, mukF, endonuclease-VIII, Rho, rpoC, yajQ, cspA, greA, t1627, dnaB and rcsB). Among these, RuvB is a helicase protein that mediates DNA Holliday junction migration by localizing the denaturation and reannealing and RecA proteins play a role in homologous recombination, promoting synapsis, heteroduplex formation, and strand exchange between homologous DNAs (Iype et al. 1994). The mukF protein is involved in chromosome condensation, which is key step for cell division (Yamazoe et al. 1999). The endonuclease-VIII (NEI) protein acts as a DNA glycosylase that recognizes and removes DNA bases damaged by oxidation or mutagenic agents (Jiang et al. 1997). Collectively, these proteins play an important role in DNA damage, DNA recombination, DNA repair, SOS response and damaged DNA binding (Igarashi and Ishihama 1991; Borukhov et al. 1992; Bae et al. 2000; Skunca et al. 2013).
RAD51 as a functional biomarker for homologous recombination deficiency in cancer: a promising addition to the HRD toolbox?
Published in Expert Review of Molecular Diagnostics, 2022
Lise M. van Wijk, Andreea B. Nilas, Harry Vrieling, Maaike P.G. Vreeswijk
A proliferating cell accumulates approximately 50 DNA DSBs per day from endogenous sources (e.g. oxidative damage, replication fork collapse, and telomere erosion) [4–7]. In addition, DNA DSBs can be induced by exogenous sources (e.g. ionizing radiation and chemotherapeutic agents). Various repair systems have evolved to deal with DSBs including non-homologous end joining (NHEJ), theta-mediated end joining (TMEJ), and homology directed repair (HDR) [8,9]. DSB repair via NHEJ, which is active during the whole cell cycle, can lead to the introduction of single nucleotide insertions and/or deletions (indels) [9]. TMEJ is active post-replication in cases where the sister chromatid cannot serve as a template. DSB repair via this pathway can result in deletions with microhomology and templated insertions [8]. During the late S/G2 phase of the cell cycle when a sister chromatid is available that may serve as repair template, DSBs can be error-free repaired by HDR [10]. Repair of DSBs is initiated by the binding of the Mre11-Rad50-Nbs1 (MRN) complex, which activates ataxia telangiectasia mutated (ATM) protein kinase causing the phosphorylation of the histone variant H2AX at Serine 139 in the vicinity of the break [11,12]. In the case of HR, accumulation of phosphorylated H2AX (γH2AX) at the site of a DSB and inhibition of 53BP1 by BRCA1 initiates the co-localization of the MRN complex, BRCA1, and CtBP-interacting protein (CtIP) promoting 5ʹ to 3ʹ DNA end resection and end processing [10]. The resected, single-strand DNA (ssDNA) ends are coated by Replication Protein A (RPA) to protect the strands from degradation. The repair process is continued with the phosphorylation of the BRCA1 protein, which forms a protein complex with PALB2 to recruit BRCA2 to the ssDNA ends. Subsequently, RPA is replaced by the RAD51 DNA recombinase through its interaction with BRCA2 to form RAD51-ssDNA nucleofilaments. These RAD51-ssDNA nucleofilaments interact with double-strand DNA (dsDNA) to scan for sequence complementarity. In a still poorly understood fashion, strand invasion and the formation of Holliday junctions occurs, a process that is promoted by the BRCA1-BARD1 complex, and DSBs are error-free repaired using the homologous sequence of the sister chromatid as template for DNA synthesis (Figure 1A) [9,13]. The inability of cells to perform HR may lead to the formation of genomic aberrations, genomic instability, and ultimately cancer [14].