Cleavage of the MLL gene by activators of apoptosis is independent of topoisomerase II activity

Betti, Christopher J.; Villalobos, Michael J.; Jiang, Qun; Cline, Edith I.; Dı́az, Manuel O.; Loredo, Grace A.; Vaughan, Andrew T M

doi:10.1038/sj.leu.2403966

Cited by 35 publications

(44 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Some translocations with leukemogenic potential are associated with recovery from initial apoptotic DNA fragmentation (20)(21)(22). The fact that ARTEMIS contributes to DNA fragmentation at early stages when apoptosis reversion is still possible suggests that ARTEMIS could play a role in such translocations.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have identified cellular intermediates and reversible apoptotic states with potential genomic instability (19); as a result, propagation of some chromosome translocations, such as those involving the MLL gene in acute and therapy-related leukemias, may rely on recovery from initial apoptotic DNA fragmentation induced by genotoxic or nongenotoxic stimuli (20)(21)(22). In addition, it has been proposed that HMW DNA fragmentation corresponds to a nucleolytic cleavage at scaffold/ matrix attachment regions in chromosomes (23).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

ARTEMIS Nuclease Facilitates Apoptotic Chromatin Cleavage

et al. 2009

View full text Add to dashboard Cite

One hallmark of apoptosis is DNA degradation that first appears as high molecular weight fragments followed by extensive internucleosomal fragmentation. During apoptosis, the DNA-dependent protein kinase (DNA-PK) is activated. DNA-PK is involved in the repair of DNA double-strand breaks (DSB) and its catalytic subunit is associated with the nuclease ARTEMIS. Here, we report that, on initiation of apoptosis in human cells by agents causing DNA DSB or by staurosporine or other agents, ARTEMIS binds to apoptotic chromatin together with DNA-PK and other DSB repair proteins. ARTEMIS recruitment to chromatin showed a time and dose dependency. It required DNA-PK protein kinase activity and was blocked by antagonizing the onset of apoptosis with a pancaspase inhibitor or on overexpression of the antiapoptotic BCL2 protein. In the absence of ARTEMIS, no defect in caspase-3, poly(ADP-ribose) polymerase-1, and XRCC4 cleavage or in H2AX phosphorylation was observed and DNA-PK catalytic subunit was still phosphorylated on S2056 in response to staurosporine. However, DNA fragmentation including high molecular weight fragmentation was delayed in ARTEMIS-deficient cells compared with cells expressing ARTEMIS. In addition, ARTEMIS enhanced the kinetics of MLL gene cleavage at a breakage cluster breakpoint that is frequently translocated in acute or therapy-related leukemias. These results show a facilitating role for ARTEMIS at least in early, site-specific chromosome breakage during apoptosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ARTEMIS Nuclease Facilitates Apoptotic Chromatin Cleavage

et al. 2009

View full text Add to dashboard Cite

show abstract

“…The use of epipodophyllotoxins in a chemotherapy regimen results in therapy-related acute leukaemia associated with translocations of the human MLL gene (Goto et al, 1994;Nasr et al, 1997). Subsequently, in vitro experiments demonstrated that certain cytotoxic drugs, topoisomerase II inhibitors, or CD95-mediated apoptosis are all able to induce DNA DSBs within SCII (Aplan et al, 1996;Stanulla et al, 1997;Felix et al, 1998;Andersen et al, 2001;Betti et al, 2001Betti et al, , 2005Sim and Liu, 2001;Libura et al, 2005). Further clues came from experiments that demonstrated DNase I hypersensitivity of SCII (Strissel et al, 1998) and elevated histone acetylation along MLL exons 11 and 14 (Khobta et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Transcription linked to recombination: a gene-internal promoter coincides with the recombination hot spot II of the human MLL gene

et al. 2006

View full text Add to dashboard Cite

The MLL gene is frequently involved in chromosomal translocations associated with high-risk acute leukaemia. Infant and therapy-related acute leukaemia patients display chromosomal breakpoints preferentially clustered in the telomeric portion of the MLL breakpoint cluster region (SCII). Here, we demonstrate that SCII colocalizes with a gene-internal promoter element in the mouse and human MLL gene, respectively. The mRNA generated encodes an N-terminally truncated version of MLL that still exhibits many functional regions, including the C-terminal SET-domain. Etoposide-induced DNA doublestrand breaks colocalize with the binding site of RNA polymerase II and the transcription initiation region, but not with a nearby Topo II consensus sequence. Thus, the observed genomic instability of the human MLL gene is presumably linked to transcriptional processes. The consequences of this novel finding for the creation of chromosomal translocations, the biology of the MLL protein and for MLL-mediated acute leukaemia are discussed.

show abstract

“…18 and 19), and mapping of VP-16-induced DSBs to the bcr of the MLL gene has led to the suggestion of a direct link between these DSBs and MLL gene translocations (8,(12)(13)(14)(15)20). However, other studies have also pointed to the involvement of apoptotic nucleases in VP-16-induced DSBs within the bcr of the MLL gene (21)(22)(23)(24)(25)(26).…”

mentioning

confidence: 99%

Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies

Azarova¹,

Lyu²,

Lin³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

261

222

View full text Add to dashboard Cite

Drugs that target DNA topoisomerase II (Top2), including etoposide (VP-16), doxorubicin, and mitoxantrone, are among the most effective anticancer drugs in clinical use. However, Top2-based chemotherapy has been associated with higher incidences of secondary malignancies, notably the development of acute myeloid leukemia in VP-16-treated patients. This association is suggestive of a link between carcinogenesis and Top2-mediated DNA damage. We show here that VP-16-induced carcinogenesis involves mainly the ␤ rather than the ␣ isozyme of Top2. In a mouse skin carcinogenesis model, the incidence of VP-16-induced melanomas in the skin of 7,12-dimethylbenz[a]anthracene-treated mice is found to be significantly higher in TOP2␤ ؉ than in skin-specific top2␤-knockout mice. Furthermore, VP-16-induced DNA sequence rearrangements and double-strand breaks (DSBs) are found to be Top2␤-dependent and preventable by cotreatment with a proteasome inhibitor, suggesting the importance of proteasomal degradation of the Top2␤-DNA cleavage complexes in VP-16-induced DNA sequence rearrangements. VP-16 cytotoxicity in transformed cells expressing both Top2 isozymes is, however, found to be primarily Top2␣-dependent. These results point to the importance of developing Top2␣-specific anticancer drugs for effective chemotherapy without the development of treatment-related secondary malignancies.DNA rearrangements ͉ melanoma ͉ skin-specific topoisomerase II␤-knockout ͉ tumor cell killing ͉ carcinogenesis A nticancer drugs that target DNA topoisomerase II (Top2), including etoposide (VP-16), doxorubicin, and mitoxantrone, are often referred to as Top2 poisons and are among the most effective and widely used anticancer drugs in the clinic. However, life-threatening toxic side effects, including drug-induced secondary malignancies, have been noted in patients receiving Top2-based chemotherapy. An association between infant leukemia and in utero exposure to Top2 poisons has also been reported (reviewed in refs. 1-3). In all cases, the molecular basis underlying carcinogenesis in Top2-based chemotherapy is unclear.Clinical evidence for a direct link between VP-16 treatment and treatment-related acute myeloid leukemia (t-AML) is particularly strong (1-3). VP-16-induced t-AML is frequently associated with balanced translocations between the mixed lineage leukemia (MLL) gene on chromosome 11q23 and Ͼ50 partner genes (the MLL gene is also known as ALL-1, hTRX, or HRX) (4-7). These rearrangements, as well as those found in infant leukemia, cluster within a well characterized 8.3-kb breakpoint cluster region (bcr) (8-16). The bcr of MLL is AT-rich and contains Alu sequences, putative recognition sites of Top2-mediated DNA cleavage, and chromosome scaffold/matrix attachment regions (SAR/MAR) (5,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). There is substantial evidence that chromosome 11q23 translocations in t-AML and infant leukemia are a consequence of drug-induced formation of double-strand breaks (DSBs) (6-9). VP-16 is known to induce DSBs by the format...

show abstract

Cleavage of the MLL gene by activators of apoptosis is independent of topoisomerase II activity

Cited by 35 publications

References 25 publications

ARTEMIS Nuclease Facilitates Apoptotic Chromatin Cleavage

ARTEMIS Nuclease Facilitates Apoptotic Chromatin Cleavage

Transcription linked to recombination: a gene-internal promoter coincides with the recombination hot spot II of the human MLL gene

Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies

Contact Info

Product

Resources

About