Chromatin structure and DNA double-strand break responses in cancer progression and therapy

Abstract

Defects in the detection and repair of DNA double-strand breaks (DSBs) have been causatively linked to tumourigenesis. Moreover, inhibition of DNA damage responses (DDR) can increase the efficacy of cancer therapies that rely on generation of damaged DNA. DDR must occur within the context of chromatin, and there have been significant advances in recent years in understanding how the modulation and manipulation of chromatin contribute to this activity. One particular covalent modification of a histone variant-the phosphorylation of H2AX-has been investigated in great detail and has been shown to have important roles in DNA DSB responses and in preventing tumourigenesis. These studies are reviewed here in the context of their relevance to cancer therapy and diagnostics. In addition, there is emerging evidence for contributions by proteins involved in mediating higher order structure to DNA DSB responses. The contributions of a subset of these proteins-linker histones and high-mobility group box (HMGB) proteins-to DDR and their potential significance in tumourigenesis are discussed.

Histone acetylation by CBP and p300 at double-strand break sites facilitates SWI/SNF chromatin remodeling and the recruitment of non-homologous end joining factors

“…In this study, we showed that siRNA-mediated ablation of TIP60, a target of anacardic acid (Sun et al, 2006), suppressed NHEJ. The results also indicated that NHEJ is accomplished through chromatin modification by HATs (Valerie and Povirk, 2003;Downs, 2007), and that this assay system can be used to examine the molecular mechanisms involved in NHEJ in vivo, including that of HATs and other chromatin remodeling proteins. ChIP analysis showed that DSB-induced acetylation of lysines 5, 8, 12 and 16 within histone H4 occurs in both yeast and mammalian cells (Downs et al, 2004;Tamburini and Tyler, 2005;Murr et al, 2006).…”

p21Waf1is required for cellular senescence but not for cell cycle arrest induced by the HDAC inhibitor sodium butyrate

“…The γH2AX foci are the markers of DNA damage breaks, incomplete DNA replication and local abnormal chromatin structure. 11,12 Although HDACI are not DNA-damaging agents, they can influence chromatin structure, DNA repair and activity of DDR signal transduction pathways. [12][13][14] The data demonstrate that untreated Waf1 +/+ and Waf1 -/-transformed cells show negligible γH2AX foci staining, which becomes evident in the course of NaB treatment (Sup.…”

The host genetic background of DNA repair mechanisms is an independent predictor of survival in diffuse large B-cell lymphoma

“…[12][13][14][15][16][17] These include drugs of the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) [18][19][20][21][22][23] as well as drugs of second-line regimens containing platinum compounds. 24,25 Tumor cells respond to DNA damage induced by chemotherapy by activating 5 major DNA repair pathways: (1) mismatch repair (MMR), [12][13][14] (2) base excision repair, [12][13][14] (3) nucleotide excision repair, [12][13][14] (4) double strand break repair, 15 and (5) direct reversal. 16 MMR, of which MLH1 is a major component, recognizes and removes mismatched or unmatched DNA base pairs or insertiondeletion loops.…”