Chromatin dynamics coupled to DNA repair

Abstract

In order to protect and preserve the integrity of the genome, eukaryotic cells have developed accurate DNA repair pathways involving a coordinated network of DNA repair and epigenetic factors. The DNA damage response has to proceed in the context of chromatin, a packaged and compact structure that is flexible enough to regulate the accession of the DNA repair machinery to DNA-damaged sites. Chromatin modifications and ATP-remodeling activities are both necessary to ensure efficient DNA repair. Here we review the current progress of research into the importance of chromatin modifications and the ATP-remodeling complex to the DNA damage response, with respect to the sensing and signaling of DNA lesions, DNA repair and the processes that restore chromatin structure.

γH2AX: a sensitive molecular marker of DNA damage and repair

“…86 Regions of chromatin affected by DSB repair are restored to their original structure and cell cycle resumes, ensuring both genetic and epigenetic information is preserved. 88 gH2AX loss has been found to correlate to repair activity only at relatively low levels of DNA damage, typically below 150 DSBs per genome and only in cells proficient in DNA repair. 27,64 At higher doses of IR, early reductions in foci number and intensity are not reflected in the global chromatin signal that remains largely unchanged.…”

When genome integrity and cell cycle decisions collide: roles of polo kinases in cellular adaptation to DNA damage

“…These sensors bind to the DNA break, and recruit large protein kinases of the phosphoinositide 3-kinase (PI3K)-like family (i.e., ATM/ATR/DNA-PKcs). The activation of these kinases leads to the phosphorylation of histone c-H2AX, contributing to the accumulation and stabilization of several checkpoint proteins at DSBs (Huertas et al 2009). Moreover, this signaling pathway results in the activation of Chk1 and Chk2 (i.e., Rad53 in yeast) effector kinases, which ultimately inhibit Cdc25 phosphatases and other cell cycle regulators.…”

Limited Repair of Critical DNA Damage in Cells Exposed to Low Dose Radiation

“…Phosphorylation of histone H2AX and other proteins by ATM, ATR and DNA-PKcs near DSB also modifies chromatin, which is crucial in the interactions between many proteins after exposure to IR and, above all, for the process of DNA repair. Thus, chromatin protein modifications contribute to active regulation of multiple reactions associated with the development of whole DDR (Goodarzi et al, 2009;Huertas et al, 2009;Costes et al, 2010). As a rule, RIF related to chromatin sites with damaged DNA in the cell nuclei are formed not immediately after irradiation.…”

“…The mechanisms of alterations of local chromatin areas related to appearance of DSB or ICL in DNA are still not clearly understood. Many studies have shown that modification of chromatin proteins by phosphorylation, methylation, acetylation, ubiquitination, sumoylation and poly ADP-ribosylation plays a critical role not only in the regulation of many genetic processes, but also in DDR development (Pandita and Richardson, 2009;Huertas et al, 2009). Decondensation of chromatin near the region of DNA DSB is considered an important trigger for ATM-dimer dissociation and subsequent autophosphorylation of ATM kinase (Goodarzi et al, 2009).…”