Regulation and localization of the Bloom syndrome protein in response to DNA damage

被引:236
作者
Bischof, O
Kim, SH
Irving, J
Beresten, S
Ellis, NA
Campisi, J
机构
[1] Univ Calif Berkeley, Lawrence Berkeley Lab, Div Life Sci, Berkeley, CA 94720 USA
[2] Berlex Labs Inc, Richmond, CA 94804 USA
[3] Mem Sloan Kettering Canc Ctr, Dept Human Genet, New York, NY 10021 USA
关键词
RECQ helicases; p53; ATM; nuclear matrix; homologous recombination;
D O I
10.1083/jcb.153.2.367
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Bloom syndrome (BS) is an autosomal recessive disorder characterized by a high incidence of cancer and genomic instability. BLM, the protein defective in BS, is a RecQ-like helicase, presumed to function in DNA replication, recombination, or repair. BLM localizes to promyelocytic leukemia protein (PML) nuclear bodies and is expressed during late S and G2. We show, in normal human cells, that the recombination/repair proteins hRAD51 and replication protein (RP)-A assembled with BLM into a fraction of PML bodies during late S/G2. Biochemical experiments suggested that BLM resides in a nuclear matrix-bound complex in which association with hRAD51 may be direct. DNA-damaging agents that cause double strand breaks and a G2 delay induced BLM by a p53- and ataxia-telangiectasia mutated independent mechanism. This induction depended on the G2 delay, because it failed to occur when G2 was prevented or bypassed. It coincided with the appearance of foci containing BLM, PML, hRAD51 and RP-A, which resembled ionizing radiation-induced foci. After radiation, foci containing BLM and PML formed at sites of single-stranded DNA and presumptive repair in normal cells, but not in cells with defective PML. Our findings suggest that BLM is part of a dynamic nuclear matrix-based complex that requires PML and functions during G2 in undamaged cells and recombinational repair after DNA damage.
引用
收藏
页码:367 / 380
页数:14
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