Journal ArticleDOI
Genome instability: a mechanistic view of its causes and consequences
TLDR
The causes and consequences of instability are reviewed with the aim of providing a mechanistic perspective on the origin of genomic instability.Abstract:
Genomic instability in the form of mutations and chromosome rearrangements is usually associated with pathological disorders, and yet it is also crucial for evolution. Two types of elements have a key role in instability leading to rearrangements: those that act in trans to prevent instability--among them are replication, repair and S-phase checkpoint factors--and those that act in cis--chromosomal hotspots of instability such as fragile sites and highly transcribed DNA sequences. Taking these elements as a guide, we review the causes and consequences of instability with the aim of providing a mechanistic perspective on the origin of genomic instability.read more
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RECQ5 helicase associates with the C-terminal repeat domain of RNA polymerase II during productive elongation phase of transcription
Radhakrishnan Kanagaraj,Daniela Huehn,April L. MacKellar,Mirco Menigatti,Lu Zheng,Vaclav Urban,Igor Shevelev,Arno L. Greenleaf,Pavel Janscak +8 more
TL;DR: Evidence is provided that RECQ5 specifically binds to the Ser2,5-phosphorylated C-terminal repeat domain (CTD) of the largest subunit of RNAPII, RPB1, by means of a Set2–Rpb1-interacting (SRI) motif located at the C- terminus of RECZ5, which supports the idea thatRECQ5 plays a role in the maintenance of genomic stability during transcription.
Journal ArticleDOI
Why eukaryotic cells use introns to enhance gene expression: Splicing reduces transcription-associated mutagenesis by inhibiting topoisomerase I cutting activity
Deng-Ke Niu,Yu-Fei Yang +1 more
TL;DR: In this article, the authors show that the serine/arginine-rich protein SF2/ASF can inhibit the DNA topoisomerase I activity that removes negative supercoiling of DNA generated by transcription.
Journal ArticleDOI
Double-strand break repair pathways protect against CAG/CTG repeat expansions, contractions and repeat-mediated chromosomal fragility in Saccharomyces cerevisiae.
TL;DR: It is concluded that failure of principal DSB repair pathways to repair breaks that occur within the repeats can result in the accumulation of atypical intermediates, whose aberrant resolution will then lead to CAG expansions, contractions, and repeat-mediated chromosomal fragility.
Journal ArticleDOI
Resolving branched DNA intermediates with structure-specific nucleases during replication in eukaryotes.
TL;DR: In eukaryotes, multiple structure-specific nucleases have been implicated in the resolution of branched DNA intermediates and it is becoming increasingly clear that, as a group, they reflect the dual function of RuvC in cleaving recombination intermediate and failing replication forks to assist the DNA replication process.
Journal ArticleDOI
Genome-wide Screen Identifies Pathways that Govern GAA/TTC Repeat Fragility and Expansions in Dividing and Nondividing Yeast Cells
Yu Zhang,Alexander A. Shishkin,Yuri Nishida,Dana Marcinkowski-Desmond,Natalie Saini,Kirill V. Volkov,Sergei M. Mirkin,Kirill S. Lobachev +7 more
TL;DR: It is demonstrated that problems imposed by the repeats during DNA replication in actively dividing cells and during transcription initiation in nondividing cells can culminate in genome instability, and proposed that similar mechanisms can mediate detrimental metabolism of GAA/TTC tracts in human cells.
References
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Book
DNA Repair and Mutagenesis
TL;DR: Nucleotide excision repair in mammalian cells: genes and proteins Mismatch repair The SOS response and recombinational repair in prokaryotes Mutagenesis in proKaryote Mutagenisation in eukaryotes Other DNA damage tolerance responses in eUKaryotes.
Journal ArticleDOI
Instability and decay of the primary structure of DNA
TL;DR: The spontaneous decay of DNA is likely to be a major factor in mutagenesis, carcinogenesis and ageing, and also sets limits for the recovery of DNA fragments from fossils.
Journal ArticleDOI
DNA Double-stranded Breaks Induce Histone H2AX Phosphorylation on Serine 139
TL;DR: In this paper, a histone H2AX species that has been phosphorylated specifically at serine 139 was found to be a major component of DNA double-stranded break.
Journal ArticleDOI
ATM Phosphorylates Histone H2AX in Response to DNA Double-strand Breaks
TL;DR: The results clearly establish ATM as the major kinase involved in the phosphorylation of H2AX and suggest that ATM is one of the earliest kinases to be activated in the cellular response to double-strand breaks.
Journal ArticleDOI
Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions
Vassilis G. Gorgoulis,Leandros-Vassilios F. Vassiliou,Panagiotis Karakaidos,Panayotis Zacharatos,Athanassios Kotsinas,Triantafillos Liloglou,Monica Venere,Richard A. DiTullio,Nikolaos G. Kastrinakis,Brynn Levy,Dimitris Kletsas,Akihiro Yoneta,Meenhard Herlyn,Christos Kittas,Thanos D. Halazonetis,Thanos D. Halazonetis +15 more
TL;DR: A panel of human lung hyperplasias, all of which retained wild-type p53 genes and had no signs of gross chromosomal instability, and found signs of a DNA damage response, including histone H2AX and Chk2 phosphorylation, p53 accumulation, focal staining of p53 binding protein 1 (53BP1) and apoptosis as discussed by the authors.