Linking histone deacetylation with the repair of DNA breaks.

Abstract

Living organisms are continually exposed to DNA damage arising from reactive species inside the cell and from environmental sources. Probably the most dangerous form of damage is the DNA doublestrand break (DSB), which interrupts both strands of the molecule. If it is not rapidly resealed, a DSB can cause aberrant chromosomal rearrangements, mutations, or cell death. To protect themselves, organisms from bacteria to humans have developed two major pathways to heal DSBs, homologous recombination (HR) and nonhomologous end-joining (NHEJ). HR utilizes an intact copy (homolog or sister chromatid) of the broken chromosome as a template for repair, whereas the NHEJ pathway joins the two ends of a DSB directly, with little or no requirement for sequence homology. Defects in either of these pathways can compromise genomic integrity and increase the potential for tumorigenesis. Recent studies indicate that, in addition to proteins that directly mediate enzymatic DNA repair, factors that organize specialized chromatin structures surrounding a DSB may facilitate DNA damage signaling and repair. It is well known that histone acetylases and histone deacetylases (HDACs) are important modifiers of chromatin and that they play a central role as transcriptional regulators. The work of Jazayeri et al. (1) in this issue of PNAS demonstrates that the Sin3p/Rpd3p deacetylase complex is required for efficient repair by NHEJ in Saccharomyces cerevisiae . This study sheds light on how chromatin, traditionally viewed as a barrier to DNA-templated processes, can be modified in a manner that increases the faithful transmission of genetic information. Highly localized changes (expansion and contraction) in chromatin structure are necessary to drive many DNA-directed processes, including transcription, replication, recombination, and repair. There are at least two classes of enzymes that promote regional changes in higher-order chromatin structure. The so-called chromatin-remodeling complexes use ATPase activity to catalyze nucleosome mobility. Chromatin structure is also …