The ACF1 Complex Is Required for DNA Double-Strand Break Repair in Human Cells

Abstract

DNA double-strand breaks (DSBs) are repaired via nonhomologous end-joining (NHEJ) or homologous recombination (HR), but cellular repair processes remain elusive. We show here that the ATP-dependent chromatin-remodeling factors, ACF1 and SNF2H, accumulate rapidly at DSBs and are required for DSB repair in human cells. If the expression of ACF1 or SNF2H is suppressed, cells become extremely sensitive to X-rays and chemical treatments producing DSBs, and DSBs remain unrepaired. ACF1 interacts directly with KU70 and is required for the accumulation of KU proteins at DSBs. The KU70/80 complex becomes physically more associated with the chromatin-remodeling factors of the CHRAC complex, which includes ACF1, SNF2H, CHRAC15, and CHRAC17, after treatments producing DSBs. Furthermore, the frequency of NHEJ as well as HR induced by DSBs in chromosomal DNA is significantly decreased in cells depleted of either of these factors. Thus, ACF1 and its complexes play important roles in DSBs repair.

Nucleosome Remodeling and Epigenetics

“…Their physiological roles are difficult to assess because of their dual potential in opening chromatin to facilitate DNA synthesis, and in subsequent nucleosome assembly to reconstitute the integrity of the nucleosome fiber. Nucleosome assembly also occurs in interphase during DNA damage repair, and many different remodelers are recruited to sites of DNA damage repair (Altaf et al 2007;Bao and Shen 2007;Downs et al 2007;Lan et al 2010).…”

Basic concepts of epigenetics

“…134,135 CHRAC subunits also include NURF, topoisomerase 136,137 and HMGB1, which are believed to lubricate areas of distorted DNA to allow smooth entry along a compact nucleosome, 138 working collectively with Acf1, which assists in DNA repair. 139 CHD/Mi2-NuRD. Repressive remodeling complexes of the SNF2-like DNA helicase/ATPase category also include NuRD, which contains Mi-2 subunits and histone deacetylases HDAC1 and HDAC2.…”

Chromatin modification and NBS1: their relationship in DNA double-strand break repair

“…SNF2h is known to form several types of complex, and several of the binding partners of these complexes have been reported to have a role in NHEJ as well as HR repair. The binding partners ACF and CHRAC directly interact with KU70, and depletion of ACF1 results in reduced accumulation of KU70 at DSB sites caused by laser microirradiation; ACF1 depletion also remarkably reduces NHEJ activity, whereas the reduction of NHEJ activity is only partial in SNF2h-depleted cells (Lan et al, 2010). The respective consequences of these depletions suggest that ACF1 functions in NHEJ through a distinct role from SNF2h.…”