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H-DNA has also been implicated in disrupting critical cellular processes, such as DNA replication and transcription.[1]

H-DNA Genetic Instability in DNA Replication

The mechanism of H-DNA formation involves the partial separation of the double helix at a homopurine-homopyrimidine mirror-repeat sequence and one of the strands folding backwards to re-anneal in the major groove.[1] This process leaves the other strand of ssDNA susceptible to attack by nucleases. One specific class of nucleases called nucleotide excision repair nucleases (NER) have been shown to interact with H-DNA in a replication-dependent and replication-independent manner. A study using human cells found that the NER nucleases ERCC1-XPF and ERCC1-XPG induced genetic instability.[2] H-DNA has been shown to induce large deletions that cause double strand breaks (DSBs) in DNA that can lead to genetic instability.[1] These deletions were less prevalent near H-DNA forming sequences in cells deficient in ERCC1-XPF and ERCC1-XPG. Alternatively, the NER nuclease FEN1 was found to suppress genetic instability. HeLa cells deficient in FEN1 showed higher prevalence of deletions near H-DNA forming sequences. In the absence of DNA replication, more mutations were found in ERCC1-XPF and ERCC1-XPG deficient cells, indicating they act in a replication-independent manner. However, H-DNA induced mutagenesis was more pronounced in the presence of DNA replication in FEN1 deficient cells, indicating it acts in a replication-dependent manner. Both mechanisms have been implicated in human cancer etiology.[2]

H-DNA in Transcription

H-DNA forming sequences can also cause genetic instability by interfering with transcription and stopping it prematurely.[1] The DNA opening involved in transcription makes it more susceptible to damage. In transcription-coupled repair (TCR), a lesion on the template strand of DNA stops the function of RNA polymerase and signals TCR factors to resolve the damage by excising it.[3] H-DNA forming sequences, like those seen in the c-MYC promoter, can be perceived as damage by the cell and can interfere with transcription.[1] A study observing transcription by T7 RNA polymerase on the c-MYC promoter found shortened transcription products that were stopped in close proximity to the H-DNA forming sequence. Formation of the triplex in this region upstream of T7 prevents it from traveling down the template strand because of the steric hindrance it causes. This stops transcription and signals for TCR factors to come resolve the triplex, which results in DNA excision that can cause genetic instability.[3] Similar results were seen when the activity of T7 was observed with a stable H-DNA forming sequence analog. Here, the formation of the triplex was helped by altering the sequence to make reforming B-DNA more difficult. When T7 was traveling downstream towards the triplex, transcription blockage was observed at the duplex-to-triplex junction. Here, the template strand was the central strand of the triplex, and the difficulty of disrupting its Watson-Crick and Hoogsteen hydrogen bonds stopped transcription from progressing.[4]

  1. ^ a b c d e Wang, Guliang; Vasquez, Karen (2017-01-05). "Effects of Replication and Transcription on DNA Structure-Related Genetic Instability". Genes. 8 (1): 17. doi:10.3390/genes8010017. ISSN 2073-4425. PMC 5295012. PMID 28067787.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  2. ^ a b Zhao, Junhua; Wang, Guliang; del Mundo, Imee M.; McKinney, Jennifer A.; Lu, Xiuli; Bacolla, Albino; Boulware, Stephen B.; Zhang, Changsheng; Zhang, Haihua; Ren, Pengyu; Freudenreich, Catherine H. (2018-01). "Distinct Mechanisms of Nuclease-Directed DNA-Structure-Induced Genetic Instability in Cancer Genomes". Cell Reports. 22 (5): 1200–1210. doi:10.1016/j.celrep.2018.01.014. PMC 6011834. PMID 29386108. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  3. ^ a b Belotserkovskii, Boris P.; De Silva, Erandi; Tornaletti, Silvia; Wang, Guliang; Vasquez, Karen M.; Hanawalt, Philip C. (2007-11-02). "A Triplex-forming Sequence from the Human c- MYC Promoter Interferes with DNA Transcription". Journal of Biological Chemistry. 282 (44): 32433–32441. doi:10.1074/jbc.M704618200. ISSN 0021-9258.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  4. ^ Pandey, Shristi; Ogloblina, Anna M.; Belotserkovskii, Boris P.; Dolinnaya, Nina G.; Yakubovskaya, Marianna G.; Mirkin, Sergei M.; Hanawalt, Philip C. (2015-08-18). "Transcription blockage by stable H-DNA analogs in vitro". Nucleic Acids Research. 43 (14): 6994–7004. doi:10.1093/nar/gkv622. ISSN 0305-1048. PMC 4538819. PMID 26101261.{{cite journal}}: CS1 maint: PMC format (link)