Regulation of DNA double-strand break repair pathway choice

Abstract

npg DNA double-strand breaks (DSBs) are critical lesions that can result in cell death or a wide variety of genetic alterations including large-or small-scale deletions, loss of heterozygosity, translocations, and chromosome loss. DSBs are repaired by non-homologous end-joining (NHEJ) and homologous recombination (HR), and defects in these pathways cause genome instability and promote tumorigenesis. DSBs arise from endogenous sources including reactive oxygen species generated during cellular metabolism, collapsed replication forks, and nucleases, and from exogenous sources including ionizing radiation and chemicals that directly or indirectly damage DNA and are commonly used in cancer therapy. The DSB repair pathways appear to compete for DSBs, but the balance between them differs widely among species, between different cell types of a single species, and during different cell cycle phases of a single cell type. Here we review the regulatory factors that regulate DSB repair by NHEJ and HR in yeast and higher eukaryotes. These factors include regulated expression and phosphorylation of repair proteins, chromatin modulation of repair factor accessibility, and the availability of homologous repair templates. While most DSB repair proteins appear to function exclusively in NHEJ or HR, a number of proteins influence both pathways, including the MRE11/RAD50/NBS1(XRS2) complex, BRCA1, histone H2AX, PARP-1, RAD18, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and ATM. DNA-PKcs plays a role in mammalian NHEJ, but it also influences HR through a complex regulatory network that may involve crosstalk with ATM, and the regulation of at least 12 proteins involved in HR that are phosphorylated by DNA-PKcs and/or ATM.

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

“…Interestingly, PARP has also been implicated in a slow alternative NHEJ pathway that is separate from the DNA-PK-dependent classical NHEJ (Audebert et al, 2004(Audebert et al, , 2008Wang et al, 2005Wang et al, , 2006Shrivastav et al, 2008;Terzoudi et al, 2008;Iliakis, 2009;Robert et al, 2009). This finding may further justify the use of PARPi in HR-deficient cancers, especially since the alternative NHEJ pathway may be enhanced in G2 (Wu et al, 2008).…”

The plant‐specific CDKB 1‐ CYCB 1 complex mediates homologous recombination repair in Arabidopsis

“…In contrast to NHEJ, HR is highly accurate since it exactly replaces the defective DNA (Shrivastav et al , 2008). HR requires a homologous template to repair the damaged DNA and can therefore only occur after DNA replication in S phase and the subsequent G2 phase of the cell cycle when sister chromatids are available.…”

Radiosensitizing Effect of TRPV1 Channel Inhibitors in Cancer Cells

“…On the other hand, HR processes use undamaged homologous DNA sequences (sister chromatid or the homologous chromosome) to ensure the fidelity of the repair process. [4][5][6] The DNA damage response pathways protect genomic integrity and act as a barrier against cancer, 7) and are important for recovery of irradiated normal cells. However, overexpression of DNA repair proteins is involved in radioresistance of cancer cells, [8][9][10] and therefore these mechanisms also decrease the efficiency of radiation therapy.…”