Adolf-Butenandt-Institute, Ludwig-Maximilians-University Munich, Germany.
Nucleic Acids Res. 2011 Oct;39(19):8445-56. doi: 10.1093/nar/gkr435. Epub 2011 Jul 11.
Active chromatin remodelling is integral to the DNA damage response in eukaryotes, as damage sensors, signalling molecules and repair enzymes gain access to lesions. A variety of nucleosome remodelling complexes is known to promote different stages of DNA repair. The nucleosome sliding factors CHRAC/ACF of Drosophila are involved in chromatin organization during development. Involvement of corresponding hACF1-containing mammalian nucleosome sliding factors in replication, transcription and very recently also non-homologous end-joining of DNA breaks have been suggested. We now found that hACF1-containing factors are more generally involved in the DNA damage response. hACF1 depletion increases apoptosis, sensitivity to radiation and compromises the G2/M arrest that is activated in response to UV- and X-rays. In the absence of hACF1, γH2AX and CHK2ph signals are diminished. hACF1 and its ATPase partner SNF2H rapidly accumulate at sites of laser-induced DNA damage. hACF1 is also required for a tight checkpoint that is induced upon replication fork collapse. ACF1-depleted cells that are challenged with aphidicolin enter mitosis despite persistence of lesions and accumulate breaks in metaphase chromosomes. hACF1-containing remodellers emerge as global facilitators of the cellular response to a variety of different types of DNA damage.
活性染色质重塑是真核生物 DNA 损伤反应的一个组成部分，因为损伤传感器、信号分子和修复酶可以获得病变部位的信息。多种核小体重塑复合物被认为可以促进 DNA 修复的不同阶段。果蝇的核小体滑动因子 CHRAC/ACF 参与了发育过程中的染色质组织。相应的含有 hACF1 的哺乳动物核小体滑动因子参与复制、转录，最近还参与了 DNA 断裂的非同源末端连接，这一点已经得到了证实。现在我们发现，含有 hACF1 的因子更普遍地参与了 DNA 损伤反应。hACF1 的缺失会增加细胞凋亡、对辐射的敏感性，并损害 UV 和 X 射线激活的 G2/M 期阻滞。在没有 hACF1 的情况下，γH2AX 和 CHK2ph 信号会减弱。hACF1 和它的 ATP 酶伴侣 SNF2H 会迅速在激光诱导的 DNA 损伤部位积累。hACF1 也被需要用于在复制叉崩溃时诱导的严格检查点。尽管存在损伤，而且中期染色体积累断裂，但受到阿霉素挑战的耗尽 ACF1 的细胞仍然进入有丝分裂。含有 hACF1 的重塑因子是细胞对各种不同类型的 DNA 损伤的反应的全局促进因子。
