Why is double stranded dna important

Sign up to join this community. The best answers are voted up and rise to the top. Stack Overflow for Teams — Collaborate and share knowledge with a private group. Create a free Team What is Teams? Learn more. Asked 7 years ago. Active 3 years, 6 months ago. Viewed 37k times.

Improve this question. This can be used to repair damages. Add a comment. Active Oldest Votes. DNA double helix allows it to be stable and it won't easily destroyed. Improve this answer. An essential step to prevent the propagation of damaged DNA, either by its replication or division amongst daughter cells, is the damage-induced suppression of cell cycle progression. In mammalian cells, initiation of checkpoint signalling is largely facilitated by two members of the PI3 kinase-related kinases family, ATM and ATR [ — ].

For both ATM and ATR, activation results in the initiation of downstream signalling, facilitating activation of effector kinases, namely Chk1 and Chk2 [ ]. Although Chk1 activation is predominantly mediated by ATR, and Chk2 activation predominantly by ATM, considerable crossover is also apparent between these pathways [ — ].

In turn, recruitment and activation of TopBPI is seen to stimulate the kinase activity of ATR, amplifying downstream signalling [ ]. SSBs function in cell cycle checkpoint activation. Activated ATR phosphorylates various cell cycle checkpoint proteins, including p53 and CHK1, allowing for cell cycle arrest. Strap, a phosphorylation substrate of ATM, interacts with and stabilises p53, and additionally directs it to transcriptional targets.

Here it interacts directly with murine double minute 2 Mdm2 , the major E3 ubiquitin ligase involved in p53 poly-ubiquitination [ ]. While suppression of p53 poly-ubiquitination immediately following damage appears to be facilitated through various post-translational means [ ], competitive ubiquitination by RFWD3 seems to present a method of stabilisation during the later phase after 2.

This may occur through the generation of smaller non-proteasome-targeting ubiquitin chains. As yet however, the mechanism through which this occurs remains unclear. In response to DNA damage, hSSB1 was suggested to bind p21 [ ], where it inhibits the ubiquitin-mediated degradation associated with the labile protein [ — ].

More recent data has indicated that hSSB1 may also function to promote p53 stabilisation through a direct interaction [ ]. Additionally, hSSB1 depletion was found to suppress pmediated acetylation of p53 [ ], an important modification associated with p53 transcriptional activity.

This was supported by the decreased expression of p21 and SULF2, two p53 transcriptional targets [ , ], following hSSB1 depletion [ ]. Recently, a novel OB-fold was reported in Strap, an important cofactor of p53 [ , ]. In response to DNA damage, ATM-mediated phosphorylation of Strap allows for nuclear accumulation of the protein, while protein stabilisation is achieved following phosphorylation by CHK2 [ , ].

This is supported by the observation that in ataxia telangiectasia cells, or cells expressing Strap mutated at the S ATM phosphorylation site, Strap is restricted to the cytoplasm [ ].

Following damage, localised Strap interacts with other components of the p coactivator complex, including p, the junction mediating and regulatory JMY protein, and protein arginine methyltransferase 5 PRMT5 [ , — ].

Such protein interactions are facilitated by both the Strap N-terminus, which contains six tetratricopeptide repeat TPR motifs [ ], as well as the C-terminus, which largely consists of the OB-fold [ ].

As part of the p complex, Strap has been shown to promote p53 activity both by promoting stabilisation of p53 through suppression of MDM2-mediated poly-ubiquitination, as well as by stimulating p53 transcription modulating activation [ ].

The replication of chromosome ends presents a unique challenge in eukaryotic cells. These structures contain telomeric DNA arranged in a series of repeats, the sequence of which varies between organisms.

While telomere repeats are re-synthesised in germ and embryonic cells by the enzyme telomerase, in somatic cells, shortening of chromosomes to a critical length causes the induction of a senescence phase [ ].

The precise length of these overhangs is fundamentally determined by the positioning of the final RNA primer, generally ranging in human cells from 30—40 nt for leading strand, and 80— nt for lagging strand, daughter chromosomes [ , ]. The presence of these overhangs offers an additional challenge for eukaryotic cells, as to prevent their degradation or deleterious recognition as a site of DNA damage, they must be in some way sequestered [ 21 ].

This is facilitated by the special arrangement of the OB-folds, where the binding grooves of each domain form a continuous channel, with both OB-folds arranged in-line [ ]. A protein-interaction function has however recently been described for the TPP1 OB-fold, where the domain was observed to bind and recruit the telomerase reverse transcriptase TERT [ — ]. Interestingly, this is in addition to the observation that POT1-TPP1 binding delays primer dissociation [ ], suggesting at least two possible mechanisms through which the dimer may function in telomere processivity.

Together, these seemingly conflicting roles may indicate the POT1-TPP1 heterodimer is involved both in the stimulation and suppression of telomerase activity, however as yet the coordination of these activities remains unclear. Such sequence-specificity is however not evident for TERF2IP, where in vitro data has demonstrated similar binding of the protein with telomeric and non-telomeric DNA [ ].

Recently this has been demonstrated by double knockout of TRF1 and 2 in mouse embryonic fibroblasts, leading to generation of shelterin-free telomeres. Here, both ATM and ATR responses were elicited against the exposed chromosome ends, as indicated by the accumulation of 53BP1 foci, CHK1 and 2 phosphorylation, and increased telomere fusion events [ ]. Here, POT1 suppression of ATR signalling was suggested to be through the steric inhibition of RPA localisation, a process described in previous sections as essential for such signalling.

Interestingly however, RPA is known to bind telomeres during S-phase where it is suggested to promote telomerase activity [ , ]. Furthermore, as each of these subunits contain putative OB-fold domains, structural and functional similarities have been drawn with the RPA heterotrimer [ , ]. An exception to this is the presence of an additional C-terminal winged helix-turn helix wHTH motif on the STN1 subunit, which confers a telomere-specific binding function [ 24 ].

Currently the end-protection role of CST remains unclear, and indeed while some authors have reported de-protection of telomeres following CST component depletion [ , ], others have suggested only a minimal effect [ , ]. Furthermore, while it seems uncontested that CST functions in telomere length control, both telomere lengthening [ ], and shortening [ ] has been reported in cells deficient of CST. As the N-terminal OB-fold of CTC1 is known to interact with telomerase [ , ], these length control functions are likely due to regulation of telomerase activity.

SSBs from the OB domain family play an essential role in the maintenance of genome stability, functioning in DNA replication, the repair of damaged DNA, the activation of cell cycle checkpoints, and in telomere maintenance. The importance of SSBs in these processes is highlighted by their ubiquitous nature in all kingdoms of life [ 1 ]. Here, in addition to genome stability maintenance, SSBs function in all known processes involving the exposure of ssDNA, such as transcriptional activation [ ].

In humans, RPA has long been known to play an important role in the processing of ssDNA, however the recent identification of hSSB1 and 2 has raised several questions regarding the coordination of these processes. Additionally, the diversity of OB-fold primary sequences has made it difficult to detect these domains by non-biophysical means, allowing for the continued identification of OB-folds in previously identified proteins.

This is highlighted by the recent identification of Strap and the RMI dimer, and suggests that further SSBs are likely to be identified. Crit Rev Biochem Mol Biol. Subcell Biochem. PLoS One. Mol Cell Biol. EMBO J.

Identification of phenylalanine 60 as the site of cross-linking. J Biol Chem. FEBS Lett. A study by optically detected magnetic resonance spectroscopy. Cation, anion, pH, and binding density effects. Binding mode transitions and equilibrium binding studies. Biochem Pharmacol. Escherichia coli SSB protein-single stranded nucleic acid interactions. J Mol Biol. Cation and anion effects and polynucleotide specificity. Biochemistry Mosc. CAS Google Scholar. Nat Struct Biol.

Protein Sci. Nat Rev Mol Cell Biol. Escherichia coli SSB tetramer binding to oligodeoxyadenylates. Effects of monovalent salts on binding enthalpy. Genes Dev. Nucleic Acids Res. J Cell Biol. Annu Rev Biochem. J Cell Sci. Curr Biol. Liu VF, Weaver DT: The ionizing radiation-induced replication protein A phosphorylation response differs between ataxia telangiectasia and normal human cells.

Mol Biol Cell. Cancer Res. Current evidence suggests that MRN has impacts on ATM signalling both upstream and downstream of ATM activation suggesting a role as a sensor but potentially also a role as a mediator protein. Tanja Paull has carried out excellent biochemical studies dissecting the process of ATM activation at the biochemical level while Martin Lavin has taken a cell-based approach.

A-T cells and patients, which harbour mutations in ATM, are exquisitely radiosensitive and indeed, A-T represents one of the most clinically radiosensitive conditions described.

For some years, it was argued that cell cycle checkpoint defects were the primary cause of A-T radiosensitivity but more recently, ATM has also been shown to regulate a component of DSB repair Riballo et al. Andre Nussenzweig in this issue will consider how the checkpoint and repair functions of ATM interplay during antigen receptor gene assembly, a process that functions during the development of the immune response, to prevent the formation and proliferation of damaged lymphocytes.

The dual deficiency of A-T cells likely underlies the highly elevated frequency of lymphoid tumours in A-T patients. Now that we have a reasonable understanding of DSB repair, research is progressing to the next stage to understand how DSBs are repaired within the context of chromatin. This encompasses how chromatin can impede the DNA damage responses as well as understanding how the DNA damage responses effect chromatin modifications to deal with the problem.

Indeed, current evidence suggests that a component of ATM signalling serves to modify chromatin structure to facilitate repair as well as to enhance the signal. Jessica Downs, in this issue, considers the DNA damage responses in the context of chromatin and the contribution of proteins that mediate changes in chromatin structure to the damage response.

The impact of DSBs on development and the consequence of defects in the damage response pathways are central, clinically important questions. These impacts extend not only from the role of the damage response pathways in maintaining genomic stability and hence in preventing carcinogenesis but additionally the pathways have roles that impact upon normal development.

Jiri Bartek will consider how the damage response mechanisms act as a barrier to tumorigenesis, which encompasses roles in preventing the formation of the initially damaged cells as well as in preventing the proliferation of pre-tumorigenic cells. Jean-Pierre Villartay discusses the process of V D J recombination and the clinical impact of mutations in NHEJ proteins in causing immunodeficiency and developmental delay.

Nijmegen breakage syndrome NBS is another disease associated with exquisite radiosensitivity and tumour predisposition. This function of the damage response proteins is further considered by Peter McKinnon. If the DSB damage response proteins function as an important barrier to tumour progression, it is perhaps not surprising that some tumours will down- or even upregulate damage response proteins.

Eckart Meese reviews genetic changes in glioblastoma, a tumour associated with pronounced radioresistance and discusses evidence that such tumours can display alterations in proteins that impact upon NHEJ. Finally, Graeme Smith and Mark O'Conner consider the current status of approaches to exploit our knowledge of the damage response pathways as drug targets. Cell : — The cellular response to general and programmed DNA double strand breaks.

DNA Repair Amst 3 : — Severe combined immunodeficiency and microcephaly in siblings with hypomorphic mutations in DNA ligase IV. Eur J Immunol 36 : — Chromosome breakage after G2 checkpoint release.

J Cell Biol : — Article Google Scholar. The nonhomologous DNA end-joining pathway is important for chromosome stability in primary fibroblasts. Curr Biol 9 : — In vivo formation and repair of DNA double-strand breaks after computed tomography examinations. DNA ligase IV mutations identified in patients exhibiting development delay and immunodeficiency. Mol Cell 8 : — Curr Biol 10 : — Mol Cell 16 : — Impairment of V D J recombination in double-strand break repair mutants.

Science : — EMBO J 22 : —