Chromosomal stability and the DNA double-stranded break connection

Abstract

Genome stability is of primary importance for the survival and proper functioning of all organisms. Double-stranded breaks in DNA are important threats to genome integrity because they can result in chromosomal aberrations that can affect, simultaneously, many genes, and lead to cell malfunctioning and cell death. These detrimental consequences are counteracted by two mechanistically distinct pathways of double-stranded break repair: homologous recombination and non-homologous end-joining. Recently, unexpected links between these double-stranded break-repair systems, and several human genome instability and cancer predisposition syndromes, have emerged. Now, interactions between both double-stranded break-repair pathways and other cellular processes, such as cell-cycle regulation and replication, are being unveiled.

The γ‐H2A.X: Is it just a surrogate marker of double‐strand breaks or much more?

“…Since most of the DSBs expose abnormal nucleotides and nonligatable ends, a few nucleotides at each end may be lost when DNA is repaired using NHEJ. Therefore, this process is considered error prone [van Gent et al, 2001]. HR is the other major pathway of DSB repair in all eukaryotes and has a distinct advantage over other mechanisms in that it uses a homologous chromosome or a sister chromatid as a template to precisely repair DSBs.…”

“…HR is the other major pathway of DSB repair in all eukaryotes and has a distinct advantage over other mechanisms in that it uses a homologous chromosome or a sister chromatid as a template to precisely repair DSBs. Thus, it is considered error-free [van Gent et al, 2001]. The first evidence for a function of H2A.X phosphorylation in DNA damage repair came from genetic studies in yeast.…”

An HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis

“…Ionizing radiation (IR) is a well-known complete carcinogen that is able to initiate and promote neoplastic progression, resulting from its induction of a broad spectrum of DNA lesions including damage to nucleotide bases, crosslinking, and DNA single-strand breaks and DNA double-strand breaks (DSBs) that impairs chromosomal stability (van Gent et al, 2001). The latent period between radiotherapy and the appearance of second primary tumor or recurrence ranges from a few years to several decades (Holm, 1990), which is particularly the case in patients treated for childhood Hodgkin's disease (Magrath, 1997;Schellong, 1998).…”

“…Defects in cell-cycle checkpoints result in genomic instability and the initiation of tumorigenesis (van Gent et al, 2001;Maser and DePinho, 2002;Rouse and Jackson, 2002;Kastan and Bartek, 2004). In eukaryotic DNA damage signaling pathways, tumor suppressor p53 and its transcriptional target CDKN1A (p21) have an essential role in monitoring cell-cycle checkpoints (Brugarolas et al, 1995;Deng et al, 1995;Bunz et al, 1998).…”

p53-induced protein with a death domain (PIDD) isoforms differentially activate nuclear factor-kappaB and caspase-2 in response to genotoxic stress

“…The latter, which can be induced by topoisomerase inhibitors as well as IR, are extremely toxic and can lead to chromosomal aberrations and genetic instability (van Gent et al, 2001). Activation of NF-kB in response to DSB depends on two parallel signaling cascades, namely those orchestrated by the PI3 kinase like ataxia-telangectasia mutated (ATM), which is activated by DSB or higher order chromatin changes (Bakkenist and Kastan, 2003) and those regulated by PIDD, which is activated by an as yet unknown signal (Janssens et al, 2005).…”