Testing Whether Defective Chromatin Assembly in S-Phase Contributes to Breast Cancer
Annual rept. 30 Sep 2003-29 Sep 2004
FOX CHASE CANCER CENTER PHILADELPHIA PA
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Cancer cells characteristically have a high frequency of genome rearrangements. Although these genome rearrangements are likely to contribute to the defective proliferation control that is characteristic of cancer cells, the cause of rearrangements is poorly understood. We used a dominant negative mutant of chromatin assembly factor-I CAF1, a complex that assembles newly synthesized DNA into nucleosomes, to inhibit S-phase chromatin assembly and found that this induced S-phase arrest. Arrest was accompanied by DNA damage. These results show, for the first time, that in human cells CAF1 activity is required for completion of S-phase and defects in chromatin assembly induce DNA damage. We propose that errors in chromatin assembly, occurring spontaneously or caused by genetic mutations or environmental agents, contribute to genome instability and cancer. Consistent with this idea, preliminary evidence indicates that chromatin assembly factors are mutated in some human cancers.
- Medicine and Medical Research