Bloom's syndrome is a rare autosomal recessive genetic disorder characterized by chromosomal aberrations, genetic instability, and cancer predisposition, all of which may be the result of abnormal signal transduction during DNA damage recognition. Here, we show that BLM is an intermediate responder to stalled DNA replication forks. BLM colocalized and physically interacted with the DNA damage response proteins 53BP1 and H2AX. Although BLM facilitated physical interaction between p53 and 53BP1, 53BP1 was required for efficient accumulation of both BLM and p53 at the sites of stalled replication. The accumulation of BLM/53BP1 foci and the physical interaction between them was independent of γ-H2AX. The active Chk1 kinase was essential for both the accurate focal colocalization of 53BP1 with BLM and the consequent stabilization of BLM. Once the ATR/Chk1- and 53BP1-mediated signal from replicational stress is received, BLM functions in multiple downstream repair processes, thereby fulfilling its role as a caretaker tumor suppressor.

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Arsenic trioxide (As 2 O 3 ) is highly effective for the treatment of acute promyelocytic leukemia, even in patients who are unresponsive to all-trans-retinoic acid therapy. As 2 O 3 is believed to function primarily by promoting apoptosis, but the underlying molecular mechanisms remain largely unknown. In this report, using cDNA arrays, we have examined the changes in gene expression profiles triggered by clinically achievable doses of As 2 O 3 in acute promyelocytic leukemia NB4 cells. CASPASE-10 expression was found to be potently induced by As 2 O 3 . Accordingly, caspase-10 activity also substantially increased in response to As 2 O 3 treatment. A selective inhibitor of caspase-10, Z-AEVD-FMK, effectively blocked caspase-3 activation and significantly attenuated As 2 O 3 -triggered apoptosis. Interestingly, the treatment of NB4 cells with As 2 O 3 markedly increased histone H3 phosphorylation at serine 10, an event that is associated with acetylation of the lysine 14 residue. Chromatin immunoprecipitation assays revealed that As 2 O 3 potently enhances histone H3 phosphoacetylation at the CASPASE-10 locus. These results suggest that the effect of As 2 O 3 on histone H3 phosphoacetylation at the CASPASE-10 gene may play an important role in the induction of apoptosis and thus contribute to its therapeutic effects on acute promyelocytic leukemia.Acute promyelocytic leukemia (APL) 1 accounts for ϳ10 -15% of adult myeloid leukemias with 3,500 -5,500 new cases diagnosed annually (1, 2). The vast majority of APL patients harbor the chromosomal translocation t(15,17)(q22;q21) involving the retinoic acid receptor ␣ (RAR␣) gene on chromosome 15 and the promyelocytic leukemia (PML) gene on chromosome 17, generally giving rise to two fusion genes, PML-RAR␣ and RAR␣-PML (1, 3). Studies using transgenic mice have demonstrated that the protein product of the PML-RAR␣ fusion gene is primarily responsible for the leukemogenic property of this characteristic translocation (4, 5). All-trans-retinoic acid (ATRA), a physiologically active derivative of vitamin A, can induce complete remission in most APL patients associated with an enhancement of differentiation pathways (6). Recent studies (7-9) have provided strong evidence that the induction of leukemia by the PML-RAR␣ protein relies on its ability to repress gene transcription by recruiting transcription repressor complexes. Pharmacological doses of ATRA stimulate the release of the transcription repressor complexes from PML-RAR␣, thereby activating the transcription of genes critical for normal granulocytic differentiation. However, ATRA is not curative, and resistance rapidly develops usually within 10 months of therapy (2, 6). Therefore, alternative therapies are necessary.Recently, As 2 O 3 was identified as a potent anti-leukemic agent for treating not only newly diagnosed but also relapsed APL patients (2, 10 -13), and it is remarkably effective in ATRA-refractory patients (2, 12). However, the mechanisms underlying its therapeutic effects are not well understood (2,...